Synthetic processes for the preparation of aminocyclohexyl ether compounds

ABSTRACT

This invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R 3 , R 4  and R 5  are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/709,355, filed Feb. 19, 2010 (now allowed); which is a divisional ofU.S. patent application Ser. No. 11/455,280, filed Jun. 15, 2006 (nowU.S. Pat. No. 7,754,897); which claims the benefit under 35 U.S.C.§119(e) of U.S. Provisional Patent Application No. 60/748,248, filedDec. 7, 2005, and U.S. Provisional Patent Application No. 60/690,989,filed Jun. 15, 2005. These applications are incorporated herein byreference in their entireties.

FIELD OF INVENTION

The present invention is generally directed toward a method for thestereoselective preparation of aminocyclohexyl ether compounds such astrans-(1R,2R)-aminocyclohexyl ether compounds and/ortrans-(1S,2S)-aminocyclohexyl ether compounds as well as variousintermediates, substrates and stereoisomers involved. In addition, thepresent invention is directed toward a method for the stereoselectivepreparation of aminocyclohexyl ether compounds such ascis-(1R,2S)-aminocyclohexyl ether compounds and/orcis-(1S,2R)-aminocyclohexyl ether compounds The compounds prepared bymethods of the present invention are useful for treating medicalconditions or disorders, including for example, cardiac arrhythmia, suchas atrial arrhythmia and ventricular arrhythmia.

BACKGROUND OF THE INVENTION

Arrhythmia is a variation from the normal rhythm of the heart beat andgenerally represents the end product of abnormal ion-channel structure,number or function. Both atrial arrhythmias and ventricular arrhythmiasare known. The major cause of fatalities resulting from cardiacarrhythmias is the subtype of ventricular arrhythmias known asventricular fibrillation (VF). Conservative estimates indicate that, inthe U.S. alone, each year over one million Americans will have a new orrecurrent coronary attack (defined as myocardial infarction or fatalcoronary heart disease). About 650,000 of these individuals will befirst heart attacks and 450,000 of these will be recurrent attacks.About one-third of the people experiencing these attacks will die as aresult. At least 250,000 individuals a year die of coronary heartdisease within 1 hour of the onset of symptoms and before they reachadequate medical aid. These are sudden deaths caused by cardiac arrest,usually resulting from ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinicalpractice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2;Kannel and Wolf, Am. Heart J. 123(1):264-7 Jan. 1992). Its prevalence islikely to increase as the population ages and it is estimated that 3-5%of patients over the age of 60 years have AF (Kannel W. B., Abbot R. D.,Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982;Wolf P. A., Abbot R. D., Kannel W. B. Stroke. 22(8):983-8, 1991). WhileAF is rarely fatal, it can impair cardiac function and is a major causeof stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A. L.,Fisher C. M., American Journal of Cardiology 40(4):509-13, 1977; Wolf P.A., Abbot R. D., Kannel W. B., Archives of Internal Medicine147(9):1561-4, 1987; Wolf P. A., Abbot R. D., Kannel W. B. Stroke.22(8):983-8, 1991; Cabin H. S., Clubb K. S., Hall C., Perlmutter R. A.,Feinstein A. R., American Journal of Cardiology 65(16):1112-6, 1990).

PCT Published Patent Applications WO 99/50225 and WO 2004/099137 andU.S. Pat. No. 7,057,053 disclose aminocyclohexylether compounds as beinguseful in the treatment of arrhythmias. Some of the compounds disclosedtherein have been found to be particularly effective in the treatmentand/or prevention of AF. However, the synthetic methods described inthese patent applications and patent and elsewhere werenon-stereoselective and led to mixture of stereoisomers. As activepharmaceutical compounds, it is often desirable that drug molecules arein stereoisomerically substantially pure form. It may not be feasible orcost effective if the correct stereoisomer has to be isolated from amixture of stereoisomers after a multi-step synthesis. Therefore, thereremains a need in the art to develop method for the preparation ofstereoisomerically substantially pure trans-aminocyclohexyl ethercompounds.

SUMMARY OF THE INVENTION

The present invention is directed to stereoselective syntheses ofcertain aminocyclohexyl ether compounds and novel intermediates preparedtherein. The present invention is also directed to specificaminocyclohexylether compounds.

Accordingly, in one aspect, this invention is directed to a method ofmaking compounds of formula (I):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof; as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably    R³, R⁴ and R⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy;    with the proviso that R³, R⁴ and R⁵ cannot all be hydrogen at the    same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises:-   a) reacting a compound of formula (4):

-   -   wherein each R^(2a) is O or H₂ where at least one R^(2a) in the        compound of formula (4) is O, and R is H, C₂-C₆acyl or an        oxygen-protecting group, with a compound of formula (5):

-   -   wherein R³, R⁴ and R⁵ are as defined above and Q is a leaving        group, to form a compound of formula (6):

-   -   wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R        is H, C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ and R⁵        are as defined above, under suitable conditions such that upon        reaction of the compound of formula (4) with the compound of        formula (5), the trans relative configuration of the hydroxyl        group on the carbon at the 1-position of the compound of        formula (4) is retained in the carbon at the 1-position of the        compound of formula (6);

-   b) reducing the compound of formula (6) under suitable conditions to    form a compound of formula (I).

This method can further comprise a deprotection step prior to thereaction of a compound of formula (4) with a compound of formula (5),wherein the deprotection step comprises treating a compound of formula(3):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R¹ is anoxygen-protecting group (preferably an optionally substituted benzylgroup) and R is H, C₂-C₅acyl or an oxygen-protecting group (preferablyC₂-C₅acyl), to suitable deprotecting conditions to form a compound offormula (4) as set forth above.

This method can further comprise a cyclization step to form a compoundof formula (3), wherein the cyclization step comprises reacting acompound of formula (7) or a compound of formula (8) or a mixture of acompound of formula (7) and a compound of formula (8):

wherein each R¹ is independently an oxygen-protecting group (preferablyan optionally substituted benzyl group), each R^(2a) is O or H₂, and Ris H, C₂-C₅acyl or an oxygen-protecting group (preferably C₂-C₅acyl),under suitable conditions to form a compound of formula (3) as set forthabove.

This method can further comprise a condensation step to form a compoundof formula (7) or a compound of formula (8) or a mixture of a compoundof formula (7) and a compound of formula (8), wherein the condensationstep comprises reacting a compound of formula (1):

where R¹ is an oxygen-protecting group (preferably an optionallysubstituted benzyl group), with a compound of formula (2a):

wherein each R^(2a) is O or H₂ where at least one R^(2a) in the compoundof formula (2a) is O, R is H, C₂-C₅acyl or an oxygen-protecting group(preferably C₂-C₅acyl), under suitable conditions to form the compoundof formula (7) or the compound of formula (8) or the mixture of acompound of formula (7) and a compound of formula (8) as set forthabove.

In another aspect, this invention is directed to a method of makingcompounds of formula (I):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof; as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably    R³, R⁴ and R⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy;    with the proviso that R³, R⁴ and R⁵ cannot all be hydrogen at the    same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises the following:-   a) reacting a compound of formula (1a):

-   -   with a compound of formula (2a):

-   -   under suitable condensation conditions to form a product;

-   b) reacting the product of a) with a compound of formula (5):

-   -   wherein Q is a leaving group and R³, R⁴ and R⁵ are as defined        above, under suitable ether coupling conditions to form a        product;

-   c) reacting the product of b) under suitable cyclization conditions    to form a compound of formula (6):

-   -   wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R        is H, C₂-C₅acyl or an oxygen-protecting group (preferably        C₂-C₅acyl) and R³, R⁴ and R⁵ are as defined above; and

-   d) reducing the compound of formula (6) under suitable conditions to    form a compound of formula (I), as set forth above.

The product of step a) above can comprise a compound of formula (9), acompound of formula (10) or a mixture of a compound of formula (9) and acompound of formula (10):

where each R^(2a) is O or H₂ and R is H, C₂-C₅acyl or anoxygen-protecting group (preferably C₂-C₅acyl).

The product of step b) above can comprise a compound of formula (11), acompound of formula (12) or a mixture of a compound of formula (11) anda compound of formula (12):

where each R^(2a) is O or H₂, R is H, C₂-C₅acyl or an oxygen-protectinggroup (preferably C₂-C₅acyl) and R³, R⁴ and R⁵ are as defined above.

In another aspect, this invention is directed to a method of makingcompounds of formula (I):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof, as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably    R³, R⁴ and R⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy;    with the proviso that R³, R⁴ and R⁵ cannot all be hydrogen at the    same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises:-   a) reacting a compound of formula (17):

-   -   wherein R³, R⁴ and R⁵ are as defined above, with a compound of        formula (2a2):

-   -   wherein R is H, C₂-C₅acyl or an oxygen-protecting group        (preferably C₂-C₅acyl), under suitable condensation conditions        to form a compound of formula (6b):

-   -   wherein R is H, C₂-C₅acyl or an oxygen-protecting group        (preferably an optionally substituted benzyl group) and R³, R⁴        and R⁵ are as defined above; and

-   b) reducing the compound of formula (6b) under suitable conditions    to form a compound of formula (I), as set forth above.

This method can further comprise a nucleophilic displacement step toform the compound of formula (17), wherein the nucleophilic displacementstep comprises treating a compound of formula (16):

wherein —OR′ is an activated leaving group (preferably optionallysubstituted alkysulfonate or optionally substituted arylsulfonate) andR³, R⁴ and R⁵ are as defined above, with an azide under suitablenucleophilic displacement and subsequent reduction conditions to form acompound of formula (17) as set forth above.

This method con further comprise a preparation step to form the compoundof formula (16), wherein the preparation step comprises reacting acompound of formula (15):

wherein R³, R⁴ and R⁵ are as described above, with an activating agent(preferably an optionally substituted alkylsulfonyl halide or anoptionally substituted arylsulfonyl halide) under suitable conditions toform the compound of formula (16) as set forth above.

This method can further comprise an asymmetric reduction step to form acompound (15), wherein the asymmetric reduction step comprises treatinga compound of formula (14):

wherein R³, R⁴ and R⁵ are as defined above, under asymmetricreduction/hydrogenation conditions to form the compound of formula (15)as set forth above.

This method can further comprise an etherification step to form acompound of formula (14), wherein the etherification step comprisestreating a compound of formula (13):

with a compound of formula (5b):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (14), as set forth above.

In another aspect, this invention is directed to a method of makingcompounds of formula (II):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof; as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably    R³, R⁴ and R⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy;    with the proviso that R³, R⁴ and R⁵ cannot all be hydrogen at the    same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises:-   a) reacting a compound of formula (20):

-   -   wherein each R^(2a) is O or H₂ where at least one R^(2a) in the        compound of formula (20) is O, and R is H, C₂-C₅acyl or an        oxygen-protecting group (preferably C₂-C₅acyl), with a compound        of formula (5):

-   -   wherein R³, R⁴ and R⁵ are as defined above and Q is a leaving        group, to form a compound of formula (21):

-   -   wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R        is H, C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ and R⁵        are as defined above, under suitable conditions such that upon        reaction of the compound of formula (20) with the compound of        formula (5), the cis relative configuration of the hydroxyl        group on the carbon at the 1-position of the compound of        formula (20) is retained in the carbon at the 1-position of the        compound of formula (21);

-   b) reducing the compound of formula (21) under suitable conditions    to form a compound of formula (II).

This method can further comprise a deprotection step prior to thereaction of a compound of formula (20) with a compound of formula (5),wherein the deprotection step comprises treating a compound of formula(19):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R¹ is anoxygen-protecting group (preferably an optionally substituted benzylgroup) and R is H, C₂-C₅acyl or an oxygen-protecting group (preferablyC₂-C₅acyl), to suitable deprotecting conditions to form a compound offormula (20) as set forth above.

This method can further comprise a cyclization step to form a compoundof formula (19), wherein the cyclization step comprises reacting acompound of formula (23) or a compound of formula (24) or a mixture of acompound of formula (23) and a compound of formula (24):

wherein each R¹ is independently an oxygen-protecting group (preferablyan optionally substituted benzyl group), each R^(2a) is O or H₂, and Ris H, C₂-C₅acyl or an oxygen-protecting group (preferably C₂-C₅acyl),under suitable conditions to form a compound of formula (19) as setforth above.

This method can further comprise a condensation step to form a compoundof formula (23) or a compound of formula (24) or a mixture of a compoundof formula (23) and a compound of formula (24), wherein the condensationstep comprises reacting a compound of formula (18):

where R¹ is an oxygen-protecting group (preferably an optionallysubstituted benzyl group), with a compound of formula (2a):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R is H,C₂-C₅acyl or an oxygen-protecting group (preferably C₂-C₅acyl), undersuitable conditions to form the compound of formula (23) or the compoundof formula (24) or the mixture of a compound of formula (23) and acompound of formula (24) as set forth above.

In another aspect, this invention is directed to a method of makingcompounds of formula (II):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof; as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably    R³, R⁴ and R⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy;    with the proviso that R³, R⁴ and R⁵ cannot all be hydrogen at the    same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises the following:-   a) reacting a compound of formula (22):

-   -   with a compound of formula (2a):

-   -   under suitable condensation conditions to form a product;

-   b) reacting the product of a) with a compound of formula (5):

-   -   wherein Q is a leaving group and R³, R⁴ and R⁵ are as defined        above, under suitable ether coupling conditions to form a        product;

-   c) reacting the product of b) under suitable cyclization conditions    to form a compound of formula (21):

-   -   wherein each R^(2a) is O or H₂, R is H, C₂-C₅acyl or an        oxygen-protecting group (preferably C₂-C₅acyl) and R³, R⁴ and R⁵        are as defined above; and

-   d) reducing the compound of formula (21) under suitable conditions    to form a compound of formula (II), as set forth above.

The product of step a) above can comprise a compound of formula (25), acompound of formula (26) or a mixture of a compound of formula (25) anda compound of formula (26):

where each R^(2a) is O or H₂ and R is H, C₂-C₅acyl or anoxygen-protecting group.

The product of step b) above can comprise a compound of formula (27), acompound of formula (28) or a mixture of a compound of formula (27) anda compound of formula (28):

where each R^(2a) is O or H₂, R is H, C₂-C₅acyl or an oxygen-protectinggroup and R³, R⁴ and R⁵ are as defined above.

In another aspect, this invention is directed to a method of makingcompounds of formula (II):

-   or a pharmaceutically acceptable salt, ester, amide, complex,    chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or    prodrug thereof, as a single stereoisomer or as a mixture thereof;    wherein:-   R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,    C₁-C₆thioalkyl, aryl or —N(R₆)R₇ (preferably R³, R⁴ and R⁵ are    independently hydrogen, hydroxy or C₁-C₆alkoxy; with the proviso    that R³, R⁴ and R⁵ cannot all be hydrogen at the same time); and-   R⁶, R⁷, R⁸, and R⁹ are each independently selected from hydrogen,    acetyl, methanesulfonyl or C₁-C₆alkyl;    which method comprises:-   a) reacting a compound of formula (33):

-   -   wherein R³, R⁴ and R⁵ are as defined above, with a compound of        formula (2a2):

-   -   wherein R is H, C₂-C₅acyl or an oxygen-protecting group        (preferably C₂-C₅acyl), under suitable condensation conditions        to form a compound of formula (21b):

-   -   wherein R is H, C₂-C₅acyl or an oxygen-protecting group        (preferably C₂-C₅acyl) and R³, R⁴ and R⁵ are as defined above;        and

-   b) reducing the compound of formula (6b) under suitable conditions    to form a compound of formula (II), as set forth above.

This method can comprise a nucleophilic displacement step to form thecompound of formula (33), wherein the nucleophilic displacement stepcomprises treating a compound of formula (32):

wherein —OR′ is an activated leaving group (preferably an optionallysubstituted alkysulfonate or an optionally substituted arylsulfonate)and R³, R⁴ and R⁵ are as defined above, with an azide under suitablenucleophilic displacement and subsequent reduction conditions to form acompound of formula (33) as set forth above.

This method can further comprise reacting a compound of formula (31):

wherein R³, R⁴ and R⁵ are as described above, with an activating agent(preferably an optionally substituted alkylsulfonyl halide or anoptionally substituted arylsulfonyl halide) under suitable conditions toform the compound of formula (32) as set forth above.

This method can further comprise a reduction step to form a compound(31), wherein the reduction step comprises treating a compound offormula (14):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (31) as set forth above.

This method can further comprise an etherification step to form acompound of formula (14), wherein the etherification step comprisestreating a compound of formula (13):

with a compound of formula (5b):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (14), as set forth above.

All of the above methods can further comprise the formation of an acidaddition salt of a compound of formula (I) or a compound of formula(II).

In another aspect, this invention is directed to intermediates andcompounds prepared by the methods disclosed herein.

In another aspect, this invention is directed to compounds of formula(I).

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is directed to methods ofstereoselectively making compounds of formula (1) and formula (II), asset forth above in the Summary of the Invention.

An understanding of the present invention may be aided by reference tothe following definitions and explanation of conventions used herein:

The compounds of formula (I) have an ether oxygen atom at position 1 ofa cyclohexane ring, and an amine nitrogen atom at position 2 of thecyclohexane ring, with other positions numbered in corresponding orderas shown below in Structure (A):

The bonds from the cyclohexane ring to the 1-oxygen and 2-nitrogen atomsin the above formula are disposed in the trans relationship. Therefore,the stereochemistry of the amine and ether substituents of thecyclohexane ring is (R,R)-trans or (S,S)-trans for thetrans-stereoisomers of the compounds of formula (I).

Following the standard chemical literature description practice and asused in this specification, a solid full bond, as illustrated above inStructure (A) and a dashed full bond, as illustrated above in Structure(A), means that the substituents, in this case the amine and ethersubstituents, are in a trans-configuration with respect to the plane ofthe cyclohexane ring.

Following the standard chemical literature description practice and asused in this specification, a full wedge bond, as illustrated below inStructure (Aa), means that the substituent bonded to the cyclohexanering by this bond, in this case the ether substituent, is above thecyclohexane ring plane as illustrated on the page in a two dimensionalrepresentation, and a dashed wedge bond, as illustrated below inStructure (Aa), means that the substituent bonded to the cyclohexanering by this bond, in this case the amine substituent, is below thecyclohexane ring plane as shown on the page in a two dimensionalrepresentation;

The compounds of formula (II) have an ether oxygen atom at position 1 ofa cyclohexane ring, and an amine nitrogen atom at position 2 of thecyclohexane ring, with other positions numbered in corresponding orderas shown below in Structure (B):

The bonds from the cyclohexane ring to the 1-oxygen and 2-nitrogen atomsin the above formula are disposed in the cis relationship. Therefore,the stereochemistry of the amine and ether substituents of thecyclohexane ring is (R,S)-cis or (S,R)-cis for the cis-stereoisomers ofthe compounds of formula (II).

Following the standard chemical literature description practice and asused in this specification, two solid full bonds, as illustrated abovein Structure (B) means that the substituents, in this case the amine andether substituents, are in a cis-configuration with respect to the planeof the cyclohexane ring.

Following the standard chemical literature description practice and asused in this specification, a full wedge bond, as illustrated below inStructure (Ba), means that the substituent bonded to the cyclohexanering by this bond, in this case the ether and the amine substituent, isabove the cyclohexane ring plane as illustrated on the page in a twodimensional representation, and a dashed wedge bond, as illlustratedbelow in Structure (Bb), means that the substituent bonded to thecyclohexane ring by this bond, in this case the ether and the aminesubstituent, is below the cyclohexane ring plane as shown on the page ina two dimensional representation;

Following the standard chemical literature description practice and asused in this specification, a wavy bond, as illustrated below in thecompound of formula (2a2), indicates that the substituent, in this casethe —OR substituent, is either below the plane of the cyclohexane ringor above the plane of the cyclohexane ring:

In the formulae depicted herein, a bond to a substituent and/or a bondthat links a molecular fragment to the remainder of a compound may beshown as intersecting one or more bonds in a ring structure. Thisindicates that the bond may be attached to any one of the atoms thatconstitutes the ring structure, so long as a hydrogen atom couldotherwise be present at that atom. Where no particular substituent(s) isidentified for a particular position in a structure, then hydrogen(s) ispresent at that position. For example, compounds of formula (I) containthe group (C):

where the group (C) is intended to encompass groups wherein any ringatom that could otherwise be substituted with hydrogen, may instead besubstituted with either R³, R⁴ or R⁵, with the proviso that each of R³,R⁴ and R⁵ appears once and only once on the ring. Ring atoms that arenot substituted with any of R³, R⁴ or R⁵ are substituted with hydrogen.

The compounds of the present invention contain at least two asymmetriccarbon atoms and thus exist as enantiomers and diastereoisomers. For thepresent invention, the words diastereomer and diastereoisomer andrelated terms are equivalent and interchangeable. Unless otherwiseindicated, the present invention includes all enantiomeric anddiastereoisomeric forms of the aminocyclohexyl ether compounds offormula (I) and compounds of formula (II). Pure stereoisomers, mixturesof enantiomers and/or diastereoisomers, and mixtures of differentcompounds of the invention are included within the present invention.Thus, compounds of formula (I) and compounds of formula (II) may occuras racemates, racemic or diastereoisomeric mixtures and as individualdiastereoisomers, or enantiomers, unless a specific stereoisomerenantiomer or diastereoisomer is identified, with all isomeric formsbeing included in the present invention. For the present invention, aracemate, diastereoisomeric or racemic mixture does not imply a 50:50mixture of stereoisomers only. Other enantiomerically ordiastereomerically enriched mixtures of varying ratios of stereoisomersare also contemplated. Unless otherwise noted, the phrase“stereoisomerically substantially pure” generally refers to thoseasymmetric carbon atoms that are described or illustrated in thestructural formulae for that compound.

The definition of stereoisomeric purity (or optical purity or chiralpurity) and related terminology and their methods of determination(e.g., Optical rotation, circular dichroism etc.) are well known in theart (see e.g., E. L. Eliel and S. H. Wilen, in Stereochemistry ofOrganic Compounds; John Wiley & Sons: New York, 1994; and referencescited therein). The phrase “stereoisomerically substantially pure”generally refers to the enrichment of one of the stereoisomers (e.g.,enantiomers or diastereoisomers) over the other stereoisomers in asample, leading to chiral enrichment and increase in optical rotationactivity of the sample. Enantiomer is one of a pair of molecular speciesthat are mirror images of each other and not superimposable. They are“mirror-image” stereoisomers. Diastereoisomers generally refer tostereoisomers not related as mirror-images. Enantiomeric excess (ee) anddiastereoisomeric excess (de) are terms generally used to refer thestereoisomeric purity (or optical purity or chiral purity) of a sampleof the compound of interest. Their definition and methods ofdetermination are well known in the art and can be found e.g., in E. L.Eliel and S. H. Wilen, in Stereochemistry of Organic Compounds; JohnWiley & Sons: New York, 1994; and references cited therein.“Stereoselectively making” refers to preparing the compound havingenantiomeric excess (ee) or diastereoisomeric excess (de).

For the present invention, enantiomeric excess (ee) or diastereoisomericexcess (de) in the range of about 50% to about 100% is contemplated. Apreferred range of enantiomeric excess (ee) or diastereoisomeric excess(de) is about 60% to about 100%. Another preferred range of enantiomericexcess (ee) or diastereoisomeric excess (de) is about 70% to about 100%.A more preferred range of enantiomeric excess (ee) or diastereoisomericexcess (de) is about 80% to about 100%. Another more preferred range ofenantiomeric excess (ee) or diastereoisomeric excess (de) is about 85%to about 100%. An even more preferred range of enantiomeric excess (ee)or diastereoisomeric excess (de) is about 90% to about 100%. Anothereven more preferred range of enantiomeric excess (ee) ordiastereoisomeric excess (de) is about 95% to about 100%. It isunderstood that the phrase “about 50% to about 100%” includes but is notlimited to all the possible percentage numbers and fractions of a numberfrom 50% to 100%. Similarly, the phrase “about 60% to about 100%”includes but is not limited to all the possible percentage numbers andfractions of a number from 60% to 100%; the phrase “about 70% to about100%” includes but is not limited to all the possible percentage numbersand fractions of a number from 70% to 100%; the phrase “about 80% toabout 100%” includes but is not limited to all the possible percentagenumbers and fractions of a number from 80% to 100%; the phrase “about85% to about 100%” includes all but is not limited to the possiblepercentage numbers and fractions of a number from 85% to 100%; thephrase “about 90% to about 100%” includes but is not limited to all thepossible percentage numbers and fractions of a number from 90% to 100%;the phrase “about 95% to about 100%” includes all but is not limited tothe possible percentage numbers and fractions of a number from 95% to100%.

As an example, and in no way limiting the generality of the above, acompound designated with the following formula:

includes at least three chiral centers (the cyclohexyl carbon bonded tothe oxygen at the 1 position, the cyclohexyl carbon bonded to thenitrogen at the 2 position, and the pyrrolidinyl carbon bonded to theoxygen at the 3′ position) and therefore has at least four separatetrans stereoisomers, which are(1R,2R)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R³-, R⁴- and R⁵-substitutedphenethoxy)cyclohexane; (1R,2R)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R³-, R⁴-and R⁵-substituted phenethoxy)cyclohexane;(1S,2S)-2-[(3R)-Hydroxypyrrolidinyl]-1-(R³-, R⁴- and R⁵-substitutedphenethoxy)cyclohexane; and (1S,2S)-2-[(3S)-Hydroxypyrrolidinyl]-1-(R³-,R⁴- and R⁵-substituted phenethoxy)cyclohexane; and, unless the contextmake plain otherwise as used in this specification, a compound havingthe formula

means a composition that includes a component that is either one of thepossible pure enantiomeric or diastereisomeric forms of the indicatedcompound or is a mixture of any two or more of the pure enantiomeric ordiastereisomeric forms, where the mixture can include any number of theenantiomeric or diastereisomeric forms in any ratio.

As an example, and in no way limiting the generality of the above,unless the context make plain otherwise as used in this specification, acompound designated with the compound name of(1R,2R)/(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexanemeans a composition that includes a component that is either one or bothof the two pure diastereomeric forms of the indicated compound (i.e.,(1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexaneor(1S,2S)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)cyclohexane)or is a mixture of the two pure diastereomeric forms, where the mixturecan include any relative amount of the two diastereomers.

The phrase “independently at each occurrence” is intended to mean (i)when any variable occurs more than one time in a compound of theinvention, the definition of that variable at each occurrence isindependent of its definition at every other occurrence; and (ii) theidentity of any one of two different variables (e.g., R³ within the setR³, R⁴ and R⁵) is selected without regard the identity of the othermember of the set. However, combinations of substituents and/orvariables are permissible only if such combinations result in compoundsthat do not violate the standard rules of chemical valency.

Certain chemical groups named herein are preceded by the shorthandnotation “C_(x)-C_(y)” where x and y indicate the lower and upper,respectively, number of carbon atoms to be found in the indicatedchemical group. For example; C₁-C₈alkyl describes an alkyl group, asdefined below, having a total of 1 to 8 carbon atoms, and C₇-C₁₂aralkyldescribes an aralkyl group, as defined below, having a total of 7 to 12carbon atoms. Occasionally, certain chemical groups named herein arepreceded by the shorthand notation “C_(z)” where z indicates the totalnumber of carbons to be found in the indicated chemical group. The totalnumber of carbons in the shorthand notation does not include carbonsthat may exist in substituents of the group described.

In accordance with the present invention and as used herein, thefollowing terms are defined to have following meanings, unlessexplicitly stated otherwise:

“Acid addition salts” generally refer to but are not limited to thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as but not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid andthe like, or acceptable Lewis acids, or organic acids such as but notlimited to acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like, and include but not limited to thosedescribed in for example: “Handbook of Pharmaceutical Salts, Properties,Selection, and Use”, P. Heinrich Stahl and Camille G. Wermuth (Eds.),Published by VHCA (Switzerland) and Wiley-VCH (FRG), 2002.

“Acyl” refers to branched or unbranched hydrocarbon fragments terminatedby a carbonyl —(C═O)— group containing the specified number of carbonatoms. Examples include acetyl (Ac) [CH₃C(═O)—, a C₂acyl] and propionyl[CH₃CH₂C(═O)—, a C₃acyl].

“Alkanoyloxy” refers to an ester substituent wherein the non-carbonyloxygen is the point of attachment to the molecule. Examples includepropanoyloxy [(CH₃CH₂C(═O)—O—, a C₃alkanoyloxy] and ethanoyloxy[CH₃C(═O)—O—, a C₂alkanoyloxy].

“Aralkanoyloxy” refers to an ester substituent wherein the non-carbonyloxygen is the point of attachment to the molecule and the estersubstituent also comprises an alkylene group wherein one of the pointsof attachment is to an aryl group. An example of an aralkanoyloxy groupis C₆H₅CH₂C(═O)—O—, a C₈aralkanoyloxy group.

“Alkoxy” refers to an oxygen (O)-atom substituted by an alkyl group, forexample, alkoxy can include but is not limited to methoxy, which mayalso be denoted as —OCH₃, —OMe or a C₁alkoxy.

“Alkoxyalkyl” refers to an alkylene group substituted with an alkoxygroup. For example, 2-methoxyethyl [CH₃OCH₂CH₂—], 1-methoxyethyl[CH₃CH(OCH₃)—] and ethoxymethyl (CH₃CH₂OCH₂—] are all C₃alkoxyalkylgroups.

“Aralkoxy” refers to an oxygen (O)-atom substituted by an aralkyl group.An example of an aralkoxy group is C₆H₅CH₂O—, a C₇aralkoxy group.

“Alkoxycarbonyl” refers to an ester substituent wherein the carbonylcarbon is the point of attachment to the molecule. Examples includeethoxycarbonyl [CH₃CH₂OC(═O)—, a C₃alkoxycarbonyl] and methoxycarbonyl[CH₃C(═O)—, a C₂alkoxycarbonyl].

“Aralkoxycarbonyl” refers to an ester substituent wherein the carbonylcarbon is the point of attachment to the molecule and the estersubstituent also comprises an alkylene group wherein one of the pointsof attachment is to an aryl group. An example of an aralkoxycarbonylgroup is C₆H₅CH₂O—C(═O)—, a C₈aralkoxycarbonyl group.

“Alkyl” refers to a branched or unbranched hydrocarbon fragmentcontaining the specified number of carbon atoms and having one point ofattachment. Examples include n-propyl (a C₃alkyl), iso-propyl (also aC₃alkyl), and t-butyl (a C₄alkyl). Methyl is represented by the symbolMe or CH₃.

“Alkylene” refers to a divalent radical which is a branched orunbranched hydrocarbon fragment containing the specified number ofcarbon atoms, and having two points of attachment. An example ispropylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Alkylcarboxy” refers to a branched or unbranched hydrocarbon fragmentterminated by a carboxylic acid group [—COOH]. Examples includecarboxymethyl [HOOC—CH₂—, a C₂alkylcarboxy] and carboxyethyl[HOOC—CH₂CH₂—, a C₃alkylcarboxy].

“Aryl” refers to aromatic groups which have at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl (also known as heteroaryl groups) and biaryl groups,all of which may be optionally substituted. Carbocyclic aryl groups aregenerally preferred in the compounds of the present invention, wherephenyl and naphthyl groups are preferred carbocyclic aryl groups.

“Aralkyl” refers to an alkylene group wherein one of the points ofattachment is to an aryl group. An example of an aralkyl group is thebenzyl group (Bn) [C₆H₅CH₂—, a C₇aralkyl group].

“Alkylsulfonyl” refers to a radical of the formula —S(O)₂R_(a) whereR_(a) is an alkyl group as defined herein. The alkylsulfonyl group maybe optionally substituted by halo or optionally substituted aryl groups,or by other suitable substituents known to one skille in the art.

“Arylsulfonyl” refers to a radical of the formula —S(O)₂R_(b) whereR_(b) is an optionally substituted aryl group as defined herein.Arylsulfonate groups include, but are not limited to, benzenesulfonategroups, mono- or poly-substituted benzenesulfonate groups, a mono- orpoly-halobenzenesulfonate groups, 2-bromobenzenesulfonate group,2,6-dichlorobenzenesulfonate group, pentafluorobenzenesulfonate group,and a 2,6-dimethylbenzenesulfonate group. The arylsulfonyl group may beoptionally substituted by halo or alkyl, or other suitable substituentsknown to one skilled in the art.

“Cycloalkyl” refers to a ring, which may be saturated or unsaturated andmonocyclic, bicyclic, or tricyclic formed entirely from carbon atoms. Anexample of a cycloalkyl group is the cyclopentenyl group (C₅H₇—), whichis a five carbon (C₅) unsaturated cycloalkyl group.

“Carbocyclic” refers to a ring which may be either an aryl ring or acycloalkyl ring, both as defined above.

“Carbocyclic aryl” refers to aromatic groups wherein the atoms whichform the aromatic ring are carbon atoms. Carbocyclic aryl groups includemonocyclic carbocyclic aryl groups such as phenyl, and bicycliccarbocyclic aryl groups such as naphthyl, all of which may be optionallysubstituted.

“Halide” or “halo” refers to —Cl, —Br, —F or —I.

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present invention.

“Heteroaryl” refers to aryl groups having from 1 to 9 carbon atoms andthe remainder of the atoms are heteroatoms, and includes thoseheterocyclic systems described in “Handbook of Chemistry and Physics,”49th edition, 1968, R. C. Weast, editor; The Chemical Rubber Co.,Cleveland, Ohio. See particularly Section C, Rules for Naming OrganicCompounds, B. Fundamental Heterocyclic Systems. Suitable heteroarylsinclude but not limited to furanyl, thienyl, pyridyl, pyrrolyl,pyrimidyl, pyrazinyl, imidazolyl, and the like.

“Hydroxyalkyl” refers to a branched or unbranched hydrocarbon fragmentbearing a hydroxy (—OH) group. Examples include hydroxymethyl (—CH₂OH, aC₁hydroxyalkyl) and 1-hydroxyethyl (—CHOHCH₃, a C₂hydroxyalkyl).

“Thioalkyl” refers to a sulfur atom substituted by an alkyl group, forexample thiomethyl(CH₃S—, a C₁thioalkyl).

“Modulating” in connection with the activity of an ion channel meansthat the activity of the ion channel may be either increased ordecreased in response to administration of a compound or composition ormethod of the present invention. Thus, the ion channel may be activated,so as to transport more ions, or may be blocked, so that fewer or noions are transported by the channel.

“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemingtons Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaroedit. 1985). For example, sterile saline and phosphate-buffered salineat physiological pH may be used. Preservatives, stabilizers, dyes andeven flavoring agents may be provided in the pharmaceutical composition.For example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid may be added as preservatives. Id. at 1449. In addition,antioxidants and suspending agents may be used. Id.

“Pharmaceutically acceptable salt” refers to salts of the compounds ofthe present invention derived from the combination of such compounds anda pharmaceutically acceptable organic or inorganic acid (acid additionsalts) or a pharmaceutically acceptable organic or inorganic base (baseaddition salts) which retain the biological effectiveness and propertiesof the compounds of the present invention and which are not biologicallyor otherwise undesirable. Examples of pharmaceutically acceptable saltinclude but not limited to those described in for example: “Handbook ofPharmaceutical Salts, Properties, Selection, and Use”, P. Heinrich Stahland Camille G. Wermuth (Eds.), Published by VHCA (Switzerland) andWiley-VCH (FRG), 2002. The compounds of the present invention may beused in either the free base or salt forms, with both forms beingconsidered as being within the scope of the present invention.

The “therapeutically effective amount” of a compound of the presentinvention will depend on the route of administration, the type ofwarm-blooded animal being treated, and the physical characteristics ofthe specific warm-blooded animal under consideration. These factors andtheir relationship to determining this amount are well known to skilledpractitioners in the medical arts. This amount and the method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize.

Compositions described herein as “containing a compound of the presentinvention” encompass compositions that may contain more than onecompound of the present invention formula.

“Clathrates” as used herein refers to substances which fix gases,liquids or compounds as inclusion complexes so that the complex may behandled in solid form and the included constituent (or “guest” molecule)subsequently releases by the action of a solvent or by melting.Clathrates used in the instant invention may be prepared fromcyclodextrins. Cyclodextrins are widely known as having the ability toform clathrates with a variety of molecules. See, for example, InclusionCompounds, edited by J. L. Atwood, J. E. D. Davies, and D. D. MacNicol,London, Orlando, Academic Press, 1984; Goldberg, I., “The Significanceof Molecular Type, Shape and Complementarity in Clathrate Inclusion”,Topics in Current Chemistry (1988), Vol. 149, pp. 2-44; Weber, E. etal., “Functional Group Assisted Clathrate Formation—Scissor-Like andRoof-Shaped Host Molecules”, Topics in Current Chemistry (1988), Vol.149, pp. 45-135; and MacNicol, D. D. et al., “Clathrates and MolecularInclusion Phenomena”, Chemical Society Reviews (1978), Vol. 7, No. 1,pp. 65-87. Conversion into cyclodextrin clathrates is known to increasethe stability and solubility of certain compounds, thereby facilitatingtheir use as pharmaceutical agents. See, for example, Saenger, W.,“Cyclodextrin Inclusion Compounds in Research and Industry”, Angew.Chem. Int. Ed. Engl. (1980), Vol. 19, pp. 344-362; U.S. Pat. No.4,886,788 (Schering AG); U.S. Pat. No. 6,355,627 (Takasago); U.S. Pat.No. 6,288,119 (Ono Pharmaceuticals); U.S. Pat. No. 6,110,969 (OnoPharmaceuticals); U.S. Pat. No. 6,235,780 (Ono Pharmaceuticals); U.S.Pat. No. 6,262,293 (Ono Pharmaceuticals); U.S. Pat. No. 6,225,347 (OnoPharmaceuticals); and U.S. Pat. No. 4,935,446 (Ono Pharmaceuticals).

“Cyclodextrin” refers to cyclic oligosaccharides consisting of at leastsix glucopyranose units which are joined together by α(1-4) linkages.The oligosaccharide ring forms a torus with the primary hydroxyl groupsof the glucose residues lying on the narrow end of the torus. Thesecondary glucopyranose hydroxyl groups are located on the wider end.Cyclodextrins have been shown to form inclusion complexes withhydrophobic molecules in aqueous solutions by binding the molecules intotheir cavities. The formation of such complexes protects the “guest”molecule from loss of evaporation, from attack by oxygen, visible andultraviolet light and from intra- and intermolecular reactions. Suchcomplexes also serve to “fix” a volatile material until the complexencounters a warm moist environment, at which point the complex willdissolve and dissociate into the guest molecule and the cyclodextrin.For purposes of this invention, the six-glucose unit containingcyclodextrin is specified as α-cyclodextrin, while the cyclodextrinswith seven and eight glucose residues are designated as β-cyclodextrinand γ-cyclodextrin, respectively. The most common alternative to thecyclodextrin nomenclature is the naming of these compounds ascycloamyloses.

The synthetic methods/procedures described herein, especially when takenwith the general knowledge in the art, provide sufficient guidance toperform the synthesis, isolation, and purification of the compounds ofthe present invention.

Compounds of the Invention

The compounds of formula (I) and (II), as set forth above in the Summaryof the Invention and prepared by the methods disclosed herein, areuseful in treating arrhythmias, particularly atrial fibrillation, asdisclosed in detail in U.S. Pat. No. 7,057,053 and PCT Published PatentApplications 99/50225 and 2004/099137.

Accordingly, in one embodiment of the invention, the compound of formula(I) prepared by the methods disclosed herein is a compound of thefollowing formula (Ia):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof, as asingle stereoisomer or as a mixture thereof.

This compound is a compound of formula (I) wherein the hydroxysubstituent on the pyrrolidinyl ring is in the 3-position, at least oneof R³, R⁴ and R⁵ is hydrogen and one of the remaining R³, R⁴ and R⁵ ismethoxy in 3-position of the phenyl ring to which they are attached andthe remaining R³, R⁴ and R⁵ is methoxy in the 4-position of the phenylring to which they are attached, and is named herein as(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol.

In another embodiment of the invention, the compound of formula (I)prepared by the methods disclosed herein is a compound selected from thegroup consisting of the following:

Structure Chemical name

(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ia))

(3R)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ib))

(3S)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ic))

(3S)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Id))

(3R)-1-[(1R,2R)-2-[2-(4-hydroxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ie))

(3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (If))

(3R)-1-[(1R,2R)-2-[2-(4-ethoxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ig))

(3R)-1-[(1R,2R)-2-[2-(3-methoxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (Ih))or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof, as a single stereoisomer or mixtures thereof.

In another embodiment of the invention, the compound of formula (I)prepared by the methods disclosed herein is selected from the groupconsisting of the following:

-   (3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3R)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3S)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3S)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3R)-1-[(1R,2R)-2,2-(4-hydroxy-3-methoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3R)-1-[(1R,2R)-2-[2-(4-ethoxy-3-methoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride; and-   (3R)-1-[(1R,2R)-2-[2-(3-ethoxy-4-methoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride.

Of the above embodiments, a preferred embodiment is(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinolmonohydrochloride, i.e., the compound of the following formula:

In another embodiment of the invention, a compound of formula (II)prepared by the methods disclosed herein is a compound of the followingformula (IIa):

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof, as a single stereoisomer or a mixture thereof.

This compound is a compound of formula (II) wherein the hydroxysubstituent on the pyrrolidinyl ring is in the 3-position, at least oneof R³, R⁴ and R⁵ is hydrogen and one of the remaining R³, R⁴ and R⁵ ismethoxy in 3-position of the phenyl ring to which they are attached andthe remaining R³, R⁴ and R⁵ is methoxy in the 4-position of the phenylring to which they are attached, and is named herein as(3R)-1-[(1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol.

In another embodiment of the invention, the compound of formula (II)prepared by the methods disclosed herein is a compound selected from thegroup consisting of the following:

Structure Chemical name

(3R)-1-[(1S,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (IIa))

(3R)-1-[(1R,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (IIb))

(3S)-1-[(1R,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (IIc))

(3S)-1-[(1S,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Compound of formula (IId))or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof, as a single stereoisomer or mixtures thereof.

In another embodiment of the invention, the compound of formula (I)prepared by the methods disclosed herein is selected from the groupconsisting of the following:

-   (3R)-1-[(1S,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3R)-1-[(1R,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride;-   (3S)-1-[(1R,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride; and-   (3S)-1-[(1S,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    monohydrochloride.

The present invention also provides protonated versions of all of thecompounds described in this specification that may be prepared by themethod of the present invention. That is, for each compound described inthis specification, the invention also includes the quaternaryprotonated amine form of the compound that may be prepared by the methodof the present invention. These quaternary protonated amine form of thecompounds may be present in the solid phase, for example in crystallineor amorphous form, and may be present in solution. These quaternaryprotonated amine form of the compounds may be associated withpharmaceutically acceptable anionic counter ions, including but notlimited to those described in for example: “Handbook of PharmaceuticalSalts, Properties, Selection, and Use”, P. Heinrich Stahl and Camille G.Wermuth (Eds.), Published by VHCA (Switzerland) and Wiley-VCH (FRG),2002.

In another embodiment of the invention, compounds of formula (II) areprepared by methods similar to those described herein for the compoundsof formula (I) using the appropriate chiral starting materials.

This invention also provides novel intermediates prepared by the methodsdisclosed herein. The intermediates prepared by the methods disclosedherein for the preparation of compounds of formula (I) are selected fromthe group consisting of the following:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof, as a single stereoisomer or a mixture thereof;wherein:

-   each R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or N(R₆)R₇; or-   each R³, R⁴ and R⁵ are independently hydrogen, hydroxy or    C₁-C₆alkoxy; with the proviso that R³, R⁴ and R⁵ cannot all be    hydrogen at the same time;-   each R⁶, R⁷, R⁸, and R⁹ are each independently selected from    hydrogen, acetyl, methanesulfonyl or C₁-C₆alkyl;-   each R^(2a) is O or H₂ where at least one R^(2a) in each compound is    O;-   each R is independently a H, C₂-C₅acyl or an oxygen-protecting    group;-   each R′ is an optionally substituted alkylsulfonyl or an optionally    substituted arylsulfonyl group; and-   each R¹ is an oxygen-protecting group.

The intermediates prepared by the methods disclosed herein for thepreparation of compounds of formula (II) are selected from the groupconsisting of the following:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof, as a single stereoisomer or a mixture thereof;wherein:

-   each R³, R⁴ and R⁵ are independently bromine, chlorine, fluorine,    carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido,    nitro, cyano, sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃,    C₂-C₇alkanoyloxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy,    C₂-C₇alkoxycarbonyl, C₁-C₆thioalkyl, aryl or —N(R₆)R₇; or-   each R³, R⁴ and R⁵ are independently hydrogen, hydroxy or    C₁-C₆alkoxy; with the proviso that R³, R⁴ and R⁵ cannot all be    hydrogen at the same time;-   each R⁶, R⁷, R⁸, and R⁹ are each independently selected from    hydrogen, acetyl, methanesulfonyl or C₁-C₆alkyl;-   each R^(2a) is O or H₂ where at least one R^(2a) in each compound is    O;-   each R is independently a H, C₂-C₅acyl or an oxygen-protecting    group;-   each R′ is an optionally substituted alkylsulfonyl or an optionally    substituted arylsulfonyl group; and-   each R¹ is an oxygen-protecting group.

Methods of the Invention

The compounds of formula (I) and formula (II) contain ether and aminofunctional groups disposed in a 1,2 arrangement on a cyclohexane ring.Accordingly, the ether and amino functional groups are disposed ineither a trans relationship relative to one another or a cisrelationship relative to one another and the plane of the cyclohexanering as shown on the page in a two dimensional representation.

The present invention provides synthetic methodology for the preparationof compounds of formula (I) and compounds of formula (II) as describedherein.

The compounds of formula (I) and formula (II) may be prepared fromaminoalcohols and alcohols by following the general methods describedbelow. Some general synthetic processes for aminocyclohexyl ethers havebeen described in WO 99/50225 and references cited therein. Otherprocesses that may be used for preparing compounds of formula (I) andformula (II) are described in PCT Published Patent Application WO2004/099137, PCT Published Patent Application WO 2005/016242, and U.S.Pat. No. 7,057,053 and other references disclosed therein.

Methods for resolution of diastereomisomeric mixtures or racemicmixtures of the compounds of formula (I) and formula (II) orintermediates prepared herein are well known in the art (e.g., E. L.Eliel and S. H. Wilen, in Stereochemistry of Organic Compounds; JohnWiley & Sons: New York, 1994; Chapter 7, and references cited therein).Suitable processes such as crystallization (e.g. preferentialcrystallization, preferential crystallization in the presence ofadditives), asymmetric transformation of racemates, chemical separation(e.g. formation and separation of diastereomers such as diastereomericsalt mixtures or the use of other resolving agents; separation viacomplexes and inclusion compounds), kinetic resolution (e.g. withtitanium tartrate catalyst), enzymatic resolution (e.g., lipasemediated) and chromatographic separation (e.g., HPLC with chiralstationary phase and/or with simulated moving bed technology, orsupercritical fluid chromatography and related techniques) are some ofthe examples that may be applied (see e.g., T. J. Ward, AnalyticalChemistry, 2002, 2863-2872).

The present invention also encompasses the preparation ofpharmaceutically acceptable salts, esters, amides, complexes, chelates,clathrates, solvates, crystalline or amorphous forms, metabolites,metabolic precursors or prodrugs of the compounds of the presentinvention. Pharmaceutically acceptable esters and amides can be preparedby reacting, respectively, a hydroxy or amino functional group with apharmaceutically acceptable organic acid, such as identified above. Aprodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which is degraded ormodified by one or more enzymatic or other in vivo processes to theparent bioactive form. Generally, a prodrug has a differentpharmacokinetic profile than the parent drug such that, for example, itis more easily absorbed across the mucosal epithelium, it has bettersalt formation or solubility and/or it has better systemic stability(e.g., an increased plasma half-life).

Those skilled in the art recognize that chemical modifications of aparent drug to yield a prodrug include: (1) terminal ester or amidederivatives, which are susceptible to being cleaved by esterases orlipases; (2) terminal peptides, which may be recognized by specific ornonspecific proteases; or (3) a derivative that causes the prodrug toaccumulate at a site of action through membrane selection, andcombinations of the above techniques. Conventional procedures for theselection and preparation of prodrug derivatives are described in H.Bundgaard, Design of Prodrugs, (1985). Those skilled in the art arewell-versed in the preparation of prodrugs and are well-aware of itsmeaning.

The present invention also encompasses the pharmaceutically acceptablecomplexes, chelates, metabolites, or metabolic precursors of thecompounds of the present invention. Information about the meaning theseterms and references to their preparation can be obtained by searchingvarious databases, for example Chemical Abstracts and the U.S. Food andDrug Administration (FDA) website. Documents such as the followings areavailable from the FDA: Guidance for Industry, “In Vivo DrugMetabolism/Drug Interaction Studies—Study Design, Data Analysis, andRecommendations for Dosing and Labeling”, U.S. Department of Health andHuman Services, Food and Drug Administration, Center for Drug Evaluationand Research (CDER), Center for Biologics Evaluation and Research(CBER), November 1999. Guidance for Industry, “In Vivo DrugMetabolism/Drug Interaction Studies in the DRUG DEVELOPMENT PROCESS:STUDIES IN VITRO”, U.S. Department of Health and Human Services, Foodand Drug Administration, Center for Drug Evaluation and Research (CDER),Center for Biologics Evaluation and Research (CBER), April 1997.

The synthetic procedures described herein, especially when taken withthe general knowledge in the art, provide sufficient guidance to thoseof ordinary skill in the art to perform the synthesis, isolation, andpurification of the compounds of the present invention. Further, it iscontemplated that the individual features of these embodiments andexamples may be combined with the features of one or more otherembodiments or examples.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (for example, t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for mercapto include —C(O)—R″ (where R″ is alkyl, arylor arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one of ordinary skill in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed.,Wiley.

Any or all of the compounds set forth in any of the Reaction Schemesherein may be converted to a pharmaceutically acceptable salt byreaction with an inorganic or organic acid under appropriate conditionsknown to one skilled in the art.

In addition, any or all of the compounds set forth in the ReactionSchemes herein may be subjected to standard deprotection conditions inorder to arrive at the desired functional group.

In addition, at any point in any of the Reaction Schemes disclosedherein, the starting material, an intermediate or a product so formedmay be subjected to a resolution process whereby individual enantiomersor diastereomers are separated into starting materials, intermediates orproducts that are in stereoisomerically substantially pure form. Theseindividual enantiomers, diastereomers or mixtures thereof, can then beused in the method disclosed in any of the Reaction Schemes herein toprepare stereoisomerically substantially pure forms of the compounds offormula (I), or mixtures thereof. Methods for resolution of racemates orother stereoisomeric mixtures are well known in the art (e.g., E. L.Eliel and S. H. Wilen, in Stereochemistry of Organic Compounds; JohnWiley & Sons: New York, 1994; Chapter 7, and references cited therein).Suitable processes may include but are not limited to separation ofstereoisomers by crystallization (e.g. preferential crystallization,preferential crystallization in the presence of additives), asymmetrictransformation of racemates or diastereomeric mixtures, chemicalseparation (e.g. formation and separation of diastereomers such asdiastereomeric salt mixtures or the use of other resolving agents;separation via complexes and inclusion compounds), kinetic resolution(e.g. with titanium tartrate catalyst), enzymatic resolution (e.g.,lipase mediated, carbonyl reductase mediated) and chromatographicseparation (e.g., HPLC with chiral stationary phase and/or withsimulated moving bed technology, or supercritical fluid chromatographyand related techniques) (see e.g., T. J. Ward, Analytical Chemistry,2002, 2863-2872).

In the following Reaction Schemes and Preparations, the following commonabbreviations and acronyms are used:

Et₂O (diethyl ether)

MTBE (methyl tert-butyl ether)

TMSOTf (trimethylsilyl triflate)

TMS-Cl (trimethylsilyl chloride)

p-TSA (para-toluenesulfonic acid).

The following Reaction Schemes provide a de novo synthesis of thepyrrolidinol ring in the compounds of formula (I) while retaining thetrans relative configuration in the starting materials.

One general method of stereoselectively preparing the compounds offormula (I) is illustrated below in Reaction Scheme 1A wherein R¹ is anoxygen-protecting group, preferably optionally substituted benzyl; R² isselected to form a compound of formula (3) upon treatment with thecompound of formula (1), followed by cyclization, and is selected, butis not limited to, the following radicals wherein the

line in the following represents the

bond between R² and the OR group in compounds of formula (2):

where each R^(2a) is O or H₂ (provided that at least one R^(2a) is O ineach structure), and each Y is halo; R is H, C₂-C₅acyl or anoxygen-protecting group; R³, R⁴ and R⁵ are as defined above in theSummary of the Invention for compounds of formula (I); and Q representsa good leaving group:

In general, the compounds of formula (I) are prepared in Reaction Scheme1A by first treating a compound of formula (1) with a compound offormula (2) in an aprotic solvent, such as toluene, dichloromethane, orethyl acetate, followed by the treatment with an cyclizing agent, suchas a C₂-C₅acyl halide or C₂-C₅acyl anhydride, at temperatures of betweenabout 0° C. to reflux temperature, preferably at reflux temperature, toform a compound of formula (3). Alternatively, a compound of formula (1)is first treated with a compound of formula (2) in an aprotic solvent toyield a corresponding intermediate, which is then treated with acyclizing agent to form compounds of formula (3). Compounds of formula(3) are then subjected to standard deprotection conditions known to oneskilled in the art, such as hydrogenation in the presence of a catalystunder appropriate conditions, to form the compound of formula (4). Thecompound of formula (4) is then treated with a compound of formula (5)under conditions such that the stereochemical spatial arrangement of thehydroxyl group of compound of formula (4) is retained in the resultingcompound of formula (6). Such conditions include, but are not limitedto, the presence of a Lewis or Brønsted acid, (for example, HBF₄,BF₃.Et₂O, TMSOTf, ZnCl, TMS-Cl, CF₃SO₃H, HCl, CH₃SO₃H, H₂SO₄, p-TSA,camphorsulfonic acid, CF₃SO₃Ag), preferably a catalytic amount of theLewis or Brønsted acid, in an aprotic solvent. The compound of formula(5) may be optionally protected prior to the treatment with compound offormula (4). The compound of formula (6) so formed is then subjected tostandard reducing conditions known to one skilled in the art to arriveat the compound of formula (I).

Alternatively, another general method of stereoselectively preparing thecompounds of formula (I) is illustrated below in Reaction Scheme 1Bwherein Q, R, R^(2a), R², R³, R⁴ and R⁵ are as defined above in ReactionScheme 1A:

In general, the compounds of formula (I) are prepared in Reaction Scheme1B by first treating a compound of formula (1a) with a compound offormula (2) in an aprotic solvent, such as toluene, dichloromethane, orethyl acetate, followed by the treatment of the resulting product with acompound of formula (5) under conditions such that upon reaction withthe compound of formula (5) the stereochemical spatial arrangement ofthe hydroxyl group at the 1-position of the compound of formula (1a) isretained in the resulting product. Such conditions include, but are notlimited to, the presence of a Lewis or Bronsted acid, (for example,HBF₄.Et₂O, BF₃.Et₂O, TMSOTf, ZnCl, TMS-Cl, CF₃SO₃H, HCl, CH₃SO₃H, H₂SO₄,p-TSA, camphorsulfonic acid, CF₃SO₃Ag), preferably a catalytic amount ofthe Lewis or Brønsted acid, in an aprotic solvent. The resulting productis then treated with a cyclizing agent, such as a C₂-C₅ acyl chloride oracetic anhydride, at temperatures of between about 0° C. to refluxtemperature, preferably at reflux temperature, to form a compound offormula (6). The compound of formula (6) so formed is then subjected tostandard reducing conditions known to one skilled in the art to arriveat the compound of formula (I).

The oxygen-protecting groups for R¹ and R can be any oxygen-protectinggroup for alcohols as set forth in T. W. Green and P. G. M. Wuts,Protective Groups in Organic Synthesis, Wiley-Interscience, New York,N.Y. (1999)(“Green”) for the protection of alcohols. Preferably theoxygen-protecting group for R¹ is an optionally substituted benzylgroup, wherein the optional substituents on the benzyl group are as setforth in Green. Preferred oxygen-protecting groups for R are C₂-C₅acylgroups. The compound of formula (1) wherein R¹ is benzyl can be obtainedfrom BASF (Switzerland) (see, PCT Published Patent Application WO96/23894). Compounds of formula (1) can also be obtained from ASDI (601Interchange Blvd. Newark, Del. 19711, USA) and ABCR GmbH & Co. KG (ImSchlehert 10, 76187 Karlsruhe, Germany) or can be prepared according tomethods known to one skilled in the art.

Compounds of formula (5) can be prepared by methods known to one skilledin the art or by methods disclosed herein. The “Q” in the compounds offormula (5) represents a good leaving group which results in theformation of a compound of formula (6) such that the trans relativeconfiguration or spatial arrangement of the hydroxyl group on the carbonat the 1-position in the compound of formula (4) or the compound offormula (1a) is retained in that of the compound of formula (6),resulting in the retention of the trans relative configuration orspatial arrangement of the amine and ether substituents on thecyclohexyl ring in the compounds of formula (1). Haloacetimidate (e.g.2,2,2-trifluoroacetimidate or 2,2,2-trichloroacetimidate) is a preferredexample of a compound of formula (5) containing a suitable Q group forthe purposes of this invention. For some compounds of the formula (4) inReaction Scheme 1A and/or the intermediates formed in Reaction Scheme1B, it may be necessary to introduce appropriate protecting groups tothe compounds of formula (5) prior to the etherification step with thecompound of formula (5) being performed. Suitable protecting groups andthe corresponding deprotection conditions are set forth in, for example,T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis,Wiley-Interscience, New York, N.Y. (1999) and references cited therein.

Other examples of suitable Q groups for the compounds of formula (5) areprovided below in Table A. (For a review of the application of variousexamples of Q in the formation of an ether compound with an alcohol see,for example, Toshima K. and Tatsuta K. Chem. Rev. 1993, 93, 1503, TsudaT., Nakamura S, and Hashimoto S. Tetrahedron Lett. 2003, 44, 6453,Martichonok V. and Whitesides G. M. J. Org. Chem., 1996, 61, 1702 andreferences cited therein). As noted below in Table A, in addition tohaloacetimidate (e.g. trihaloacetimidate such as2,2,2-trifluoroacetimidate or 2,2,2-trichloroacetimidate) and otherimidate esters (e.g. pentafluorobenzimidate), other examples of suitableQ groups for the compounds of formula (5), include, but are not limitedto, O-carbonates and S-carbonates, including imidazole carbonates andimidazolethiocarbonates. Phosphate examples of a Q group include adiphenyl phosphate, a diphenylphosphineimidate, a phosphoroamidate and aO-sulfonyl group.

TABLE A Examples of Q

Compounds of formula (2) are chosen to yield compounds of formula (3) inReaction Scheme 1A and compounds of formula (6) in Reaction Scheme 1Babove. Examples of compounds of formula (2) include, but are not limitedto, the following compounds:

wherein R is an oxygen-protecting group; each R^(2a) is O or H₂, whereat least one R^(2a) group in each structure is O, and Y is halo.Compounds of formula (2a) can be prepared, for example, from malic acidand C₂-C₅acyl chloride according to the procedures described in Henrot,S. et al., Synthetic Communications 1986, 16(2), 183-190, or can beprepared according to methods known to one skilled in the art. Compoundsof formula (2b) are commercially available or can be prepared accordingto methods known to one skilled in the art. Additional protection anddeprotection steps, depending on the blocking groups, may be necessaryto arrive at the desired product.

Several of the steps disclosed in the above Reaction Scheme 1A orReaction Scheme 1B may be combined without isolation of the product soformed or removal of the solvent. Specific examples of such “one-pot”synthesis are disclosed herein.

The advantages of the above Reaction Scheme 1A and Reaction Scheme 1Bover published processes for preparing compounds of formula (I) are asfollows:

1. Each reaction step can be easily monitored by HPLC.

2. The overall yield of compound of formula (I) is greater than theoverall yield of compound of formula (I) in the published processes forcompounds of formula (I).

3. Only a catalytic amount of acid is needed for the etherification stepinstead of a supra-stoichiometric amount (>1 eq), although astoichiometric or suprastoichiometric amount of acid can be used.

4. Several steps can be combined in one reaction vessel which wouldreduce processing time and production plant usage.

5. The process is an efficient enantioselective process in that noundesired isomers are generated, thereby avoiding costly resolutionsteps, or the loss of costly material in the form of undesired isomers.

A more specific method of stereoselectively preparing the compounds offormula (I) as set forth above in Reaction Scheme 1A is illustratedbelow in Reaction Scheme 1A1 for the preparation of compounds of formula(I) wherein R is C₂-C₅acyl; each R^(2a) is O or H₂ where at least oneR^(2a) in each structure is O; R³, R⁴ and R⁵ are as defined above in theSummary of the Invention for compounds of formula (i); AcCl representsC₂-C₅acyl chloride; R¹ represents an oxygen-protecting group, preferablyoptionally substituted benzyl, and Q represents a leaving group:

In general, the amine of formula (1) is first condensed with a compoundof formula (2a) in a suitable solvent (such as toluene, dichloromethane,or ethyl acetate) to give compound of formula (7) or formula (8). Whenthe N-acylation of compound of formula (1) was shown to be complete byHPLC, the solvent was removed under vacuum. The mixture of the compoundsof formula (7)/(8) was refluxed in an C₂-C₅acyl halide, preferablyacetyl chloride, to effect cyclization to give succinimide of formula(3) according to the procedures smiliar to those described in Naylor, A.et al., 4-[(Alkylamino)methyl]furo[3,2-c]pyridines: A New Series ofSelective K-Receptor Agonists, J. Med. Chem. (1994), 37, 2138-2144.Addition of an C₂-C₅acyl halide, preferably acetyl chloride, to themixture of the compounds of formula (7)/(8) without first removing thesolvent was shown to also be useful for cyclization.

After the removal of excess acetyl chloride, compound of formula (3) wasthen subjected to standard hydrogenolysis condition (Pd/C—H₂-in asuitable solvent, such as toluene, methanol, ethyl acetate, Ra—Ni—H₂,Pt/C—H₂) at ambient temperature to remove the oxygen-protecting group togive compound of formula (4). Etherification of compound of formula (4)with compound of formula (5) under catalytic Lewis acid conditions(e.g., HBF₄ etherate) gave the corresponding imido-ether of formula (6).Finally, successive reduction of compound of formula (6) with a suitablereducing agent, for example, for example, borane, NaBH₄/Lewis acid,KBH₄, Red-Al (see, e.g., Alimardanov et al., Org. Proc. Res. & Dev.(2004), 8, 834-837) or lithium aluminum hydride (see, e.g., Naylor, A.et al. cited above), provided the compound of formula (I) as a freebase. Subsequent treatment of the compound of formula (I) with hydrogenchloride in diethyl ether and trituration in ethyl acetate gave thehydrochloride salt of the compound of formula (I).

Alternatively, the steps in the above Reaction Scheme may be performedwithout isolation of the intermediates and/or without removal of solvent(i.e., without solvent exchange) to form the compound of formula (6),which can then be treated as set forth above to form the compound offormula (I). An example of this alternative preparation of a compound offormula (I) is described in more detail below in the Preparations.

A more specific method of stereoselectively preparing the compounds offormula (I) as set forth above in Reaction Scheme 1A is illustratedbelow in Reaction Scheme 1A2 for the preparation of the compound offormula (Ia), which is a compound of formula (I), where R¹ represents anoxygen-protecting group, preferably optionally substituted benzyl, andAc represents acetyl:

The specific experimental conditions and parameters for the aboveReaction Scheme 1A2 are described in more detail below in thePreparations. It is also understood, in light of this disclosure, thatthe following compounds of formula (Ib), formula (Ic), formula (Id),formula (Ie), formula (If), formula (Ig) and formula (Ih), and theirpharmaceutically acceptable salts, can be prepared in a similar manneras described above and below in the Preparations for compounds offormula (Ia) and its pharmaceutically acceptable salt by utilizing theappropriate starting materials and reagents:

A more specific method of stereoselectively preparing the compounds offormula (I) as set forth above in Reaction Scheme 1B is illustratedbelow in Reaction Scheme 1B1 for the preparation of compounds of formula(I) where R is an oxygen protecting group; Ac is C₂-C₅acyl; each R^(2a)is O or H₂ where at least one R^(2a) in each structure is O; R³, R⁴ andR⁵ are as defined above in the Summary of the Invention and Q representsa leaving group:

The starting material, trans-aminocyclohexanol (compound of formula(Ia)), can be prepared from a mixture of cis- and trans-stereoisomers bystandard resolution techniques or by methods known to one skilled in theart. In general, the method disclosed in Reaction Scheme 1B1 is a“one-pot” process of acylation, acetimidate ether coupling, andcyclization, i.e., the process does not require the isolation ofintermediates from the reaction mixture and/or the removal of solvents,to give compound of formula (6), which is then subjected to standardreducing conditions to form the compound of formula (I). Morespecifically, the acylation was accomplished using 1.05 equivalents ofthe compound of formula (2a) at ambient temperature in a suitablesolvent such as toluene, dichloromethane, or ethyl acetate. The additionof compound of formula (5), preferably trichloroacetimidate, and then acatalytic amount of a Lewis acid, preferably tetrafluoroboric acidetherate, yielded a mixture of components in which the desired materialcould be identified by HPLC. The reaction mixture was then treated withan C₂-C₅acyl halide, preferably acetyl chloride, and refluxed for 1 hourto give the imido ether of formula (6), which was isolated from thereaction mixture by standard isolation techniques, such as flash columnchromatography. Subsequent reduction of the compound of formula (6) andtreatment under standard acid addition salt formation, such as treatmentwith hydrogen chloride in diethyl ether and trituration in ethylacetate, gave the salt, preferably the hydrochloride salt, of thecompound of formula (I).

Alternatively, Reaction Scheme 1B may be performed as shown below inReaction Scheme 1B2 where R is C₂-C₅acyl; each R^(2a) is O or H₂ whereat least one R^(2a) in each structure is O; R³, R⁴ and R⁵ are as definedabove in the Summary of the Invention and Q represents a leaving group:

Briefly, the acylation of the starting material (1a) was accomplished bycondensing the compound with the anhydride of formula (2a) undersuitable condensation conditions, such as ambient temperature indichloromethane, to give a mixture of the compounds of formula (9) andformula (10). The mixture of these compounds was then treated with acompound of formula (5), followed by the addition of a catalytic amountof a Lewis acid, preferably tetrafluoroboric acid etherate, undersuitable conditions to yield a mixture of compounds of formula (11) andformula (12). The mixture of these compounds was then treated undersuitable cyclization conditions, such as treatment with a cyclizingagent, such as acetyl chloride, and refluxed for 1 hour to give thecompound of formula (6), which was isolated from the reaction mixture bystandard isolation techniques, such as flash column chromatography.Subsequent treatment of the compound of formula (6) under standardreducing conditions provided the compound of formula (I), which was thentreated under standard acid addition salt formation conditions, such astreatment with hydrogen chloride in diethyl ether and trituration inethyl acetate, to give the salt, preferably the hydrochloride salt, ofthe compound of formula (I).

Compounds of formula (I) can also be stereoselectively prepared byanother method of the invention as shown below in Reaction Scheme 1Cwhere R is C₂-C₅acyl, R′ is an optionally substituted alkylsulfonyl oran optionally substituted arylsulfonyl group, X is a halide, R³, R⁴ andR⁵ are as defined above in the Summary of the Invention:

The starting material, 2-chlorocyclohexanone (13), is commerciallyavailable, for example, from Aldrich Chemical Co.

In general, 2-chlorocyclohexanone (13) was readily transformed into thecorresponding keto-ether of formula (14) by reaction with the sodiumalkoxide ion of 3,4-dimethoxyphenethyl alcohol of formula (5b) undersuitable conditions. Asymmetric reduction using the process disclosed inU.S. Pat. No. 6,617,475 or the chiral ruthenium catalyst under Noyori'sreaction conditions (see, e.g., Ohkmura, T. et al., J. Org. Chem.(1996), Vol. 61, pp. 4872) gave compound of formula (15). Compound offormula (15) was then converted into the compound (16) under suitableconditions such that —OR′ becomes an activated leaving group, such asthe treatment of the compound of formula (15) with a compound of theformula R′X, where R′ is an optionally substituted alkylsulfonyl or anoptionally substituted arylsulfonyl group and X is a halide, under basicconditions. The leaving group (—O—R′) in compound of formula (16) maybe, but is not limited to, an optionally substituted alkanesulfonatesuch as a trifluoromethanesulfonate group (CF₃SO₃—) or a mesylate group(MsO—), an optionally substituted arylsulfonate such as abenzenesulfonate group (PhSO₃—), a mono- or poly-substitutedbenzenesulfonate group, a mono- or poly-halobenzenesulfonate group, a2-bromobenzenesulfonate group, a 2,6-dichlorobenzenesulfonate group, apentafluorobenzenesulfonate group, a 2,6-dimethylbenzenesulfonate group,a tosylate group (TsO—) or a nosylate (NsO—), or other equivalent goodleaving groups. The hydroxy group in the compound of formula (15) mayalso be converted into other suitable leaving groups according toprocedures well known in the art. The leaving group may be any suitableleaving group on reaction with a nucleophilic reactant with inversion ofstereochemical configuration known in the art, including but not limitedto compounds disclosed in M. B. Smith and J. March in “March's AdvancedOrganic Chemistry”, Fifth edition, Chapter 10, John Wiley & Sons, Inc.,New York, N.Y. (2001). Treatment of the compound of formula (16) undernucleophilic displacement (SN2) conditions using sodium azide, followedby hydrogenation in the presence of a palladium catalyst provided thecompound of formula (17). The compound of formula (17) was thencondensed with substituted malic anhydride of formula (2a2) indichloromethane to give the compound of formula (6b), which was thensubjected to standard reducing conditions described herein to providethe compound of formula (I), which is then treated under standard acidaddition salt formation conditions, such as treatment with hydrogenchloride in diethyl ether and trituration in ethyl acetate, to give thesalt, preferably the hydrochloride salt, of the compound of formula (I).

The following Reaction Schemes provide a de novo synthesis of thepyrrolidinol ring in the compounds of formula (II) while retaining thecis relative configuration in the starting materials.

In general, compounds of formula (II) as set forth above in the Summaryof the Invention can be prepared in a similar manner as described abovein Reaction Scheme 1A and Reaction Scheme 1B using the followingstarting material, respectively:

The same reagents and conditions that were employed to make thecompounds of formula (I) in the foregoing Reaction Schemes may be usedto make the compounds of formula (II) from the above starting materials.For example, compounds of formula (II) may be prepared as set forth inthe following Reaction Scheme 2A wherein the cyclizing agent, thecompounds of formula (2), and R, R¹, R², R^(2a), R³, R⁴, R⁵ and Q aredefined as in Reaction Scheme 1A above:

In general, compounds of formula (II) can be prepared as set forth abovein Reaction Scheme 2A in a similar manner as the preparation ofcompounds of formula (I) as set forth abov in Reaction Scheme 1A.

Alternatively, another general method of stereoselectively preparing thecompounds of formula (II) is illustrated below in Reaction Scheme 2Bwherein Q, R, R^(2a), R³, R⁴ and R⁵ are as defined above in ReactionScheme 2A:

In general, compounds of formula (II) can be prepared by Reaction Scheme2B above in a similar manner as the preparation of compounds of formula(1) in Reaction Scheme 1B above.

In both Reaction Scheme 2A and Reaction Scheme 2B, the “Q” in thecompounds of formula (5) represents a good leaving group which resultsin the formation of a compound of formula (21) such that the cisrelative configuration or spatial arrangement of the hydroxyl group onthe carbon at the 1-position in the compound of formula (20) or thecompound of formula (22) is retained in that of the compound of formula(21), resulting in the retention of the cis relative configuration orspatial arrangement of the amine and ether substituents on thecyclohexyl ring in the compounds of formula (II).

A more specific method of stereoselectively preparing the compounds offormula (II) as set forth in Reaction Scheme 2A above is illustratedbelow in Reaction Scheme 2A1 wherein R, R^(2a), R³, R⁴, R⁵, AcCl, R¹,and Q are as defined above for Reaction Scheme 1A1:

In general, compounds of formula (II) are prepared by the methoddisclosed above in Reaction Scheme 2A1 in the same manner as thecompounds of formula (1) are prepared in Reaction Scheme 1A1.

Alternatively, the steps in the above Reaction Scheme may be performedwithout isolation of the intermediates and/or without removal of thesolvent (i.e., without solvent exchange) to form the compound of formula(21), which can then be treated as set forth above to form the compoundof formula (II).

A more specific method of stereoselectively preparing the compounds offormula (II) as set forth above in Reaction Scheme 2A is illustratedbelow in Reaction Scheme 2A2 for the preparation of the compound offormula (IIa), which is a compound of formula (II), where R¹ representsan oxygen-protecting group, preferably optionally substituted benzyl,and Ac represents acetyl:

In general, the compound of formula (IIa) can be prepared in ReactionScheme 2A2 above in a similar manner as the compounds of formula (I) areprepared in Reaction Scheme 1A2 above. It is understood that, in lightof this disclosure, the following compounds of formula (IIb), formula(IIc) and formula (IId) can be prepared in a similar manner as describedabove by utilizing the appropriate starting materials and reagents:

A more specific method of stereoselectively preparing the compounds offormula (II) as set forth above in Reaction Scheme 2B is illustratedbelow in Reaction Scheme 2B1 for the preparation of compounds of formula(II) where R, Ac, R^(2a), R³, R⁴, R⁵ and Q are defined as above inReaction Scheme 1B1:

In general, compounds of formula (II) can be prepared by the methodshown above in Reaction Scheme 2B1 in a similar manner as thepreparation of compounds of formula (1) set forth above in ReactionScheme 1B1.

Alternatively, Reaction Scheme 2B may be carried out as shown below inReaction Scheme 2B2 where R, R^(2a), R³, R⁴, R⁵ and Q are defined asabove in Reaction Scheme 1B2:

In general, compounds of formula (II) can be prepared as set forth abovein Reaction Scheme 2B2 in a similar manner as the preparation ofcompounds of formula (I) set forth above in Reaction Scheme 1B2.

Compounds of formula (II) can also be stereoselectively prepared byanother method of the invention as shown below in Reaction Scheme 2Cwhere R is C₂-C₅acyl, R′ is an optionally substituted alkylsulfonyl oran optionally substituted arylsulfonyl group, R³, R⁴ and R⁵ are asdefined above in the Summary of the Invention:

In general, compounds of formula (II) can be prepared by the methoddisclosed above for Reaction Scheme 2C in a manner similar to thatdescribed above for the preparation of compounds of formula (I) as setforth in Reaction Scheme 1C except that, instead of an asymmetricreduction step followed by hydrogenation to produce the correspondingintermediate of formula (15) in Reaction Scheme 1C, the compound offormula (14) in Reaction Scheme 2C above may be treated under standardreduction conditions, such as treatment with a reducing agent,preferably NaBH₄, to produce compound of formula (31), which is thenconverted into the activated compound of formula (32). Compound offormula (32) is then treated in a similar manner as the compound offormula (16) in Reaction Scheme 1C to produce the compound of formula(II).

The following preparations are offered by way of illustration and not byway of limitation. Unless otherwise specified, starting materials andreagents may be obtained from well-known commercial supply houses, e.g.,Sigma-Aldrich Fine Chemicals (St. Louis, Mo.), and are of standard gradeand purity; or may be obtained by procedures described in the art oradapted therefrom, where suitable procedures may be identified throughthe Chemical Abstracts and Indices therefor, as developed and publishedby the American Chemical Society (Washington, D.C.).

Preparation 1 2-(R)-Acetoxy-N-(2R-benzyloxycyclohexyl]succinamic acid(7a) or 3-(R)-acetoxy-N-(2R-benzyloxycyclohexyl)succinamic acid (8a)

To a stirred solution of (1R,2R)-2-benzyloxycyclohexylamine (1) (BASF,WO 96/23894, CAS Registry No. 216394-06-8, 0.80 g, 3.90 mmol) inanhydrous dichloromethane (10 mL) was added 2R-acetoxysuccinic anhydride(2a1) (781 mg, 4.94 mmol) in small portions. The reaction was left tostir at ambient temperature under inert atmosphere until totalconsumption of the starting material was observed by HPLC. When thereaction was deemed complete, the volatiles were removed under vacuum togive (7a)/(8a) as a white solid (1.45 g, quantitative yield); MS (ES+)364.2 [M+H]⁺, 386.2 [M+Na]⁺, 727.4 [2M+H]⁺, 749.4 [2M+Na]⁺; MS (ES−)362.1 [M]⁻, 725.3 [2M]⁻¹; ¹H-NMR (400 MHz, CDCl₃) δ 1.12-1.41 (m, 4H),1.58-1.61 (m, 1H), 1.73-1.76 (m, 1H), 2.02 (s, 3H, CH₃), 2.08-2.19 (m,2H), 2.88 (d, 1H, J=5.6 Hz), 3.19-3.28 (m, 1H), 3.72-3.81 (m, 1H),4.37-4.41 (m, 1H), 4.58-4.63 (m, 1H), 5.34-5.38 (m, 1H), 6.29 (d, 1H,J=7.6 Hz), 7.21-7.34 (m, 5H); ¹³C-NMR (100 MHz, CDCl₃) δ 20.72, 23.68,23.93, 29.91, 30.68, 36.24, 52.99, 69.68, 69.82, 69.85, 78.84, 127.59,127.63, 127.77, 127.80, 128.34, 128.39, 128.51, 138.42, 168.55, 169.60,173.48.

Preparation 2(3R)-1-((1R,2R)-2-benzyloxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (3a)

2R- or 3R-Acetoxy-N-(2R-benzyloxycyclohexyl)succinamic acid (7a)/(8a)(1.40 g, 3.85 mmol) was dissolved in acetyl chloride (15 mL). Theresultant homogenous solution was refluxed at 60° C. for 45 minutes.Volatiles were removed under vacuum and the resultant residue wasfurther dried under high vacuum to give(3R)-1-((1R,2R)-2-benzyloxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (3a) as a clear, pale yellow syrup; MS (ES+) 346.1 [M+H]⁺, 363.2[M+H₂O]⁺, 368.1 [M+Na]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 1.24-1.32 (m, 3H),1.66-1.80 (m, 3H), 2.10 (s, 3H), 2.12-2.29 (m, 2H), 2.40-2.45 (m, 1H),2.88-2.96 (m, 1H), 3.95-4.07 (m, 2H), 4.23-4.27 (m, 1H), 4.57-4.61 (m,1H), 5.05 (br s, 1H), 7.18-7.20 (m, 2H), 7.23-7.31 (m, 3H); ¹³C-NMR (100MHz, CDCl₃) δ 20.58, 23.90, 24.89, 27.87, 31.32, 35.39, 56.12, 66.78,70.54, 75.64, 127.50, 128.27, 128.99, 138.83, 169.71, 173.33, 173.49.

Preparation 3(3R)-1-((1R,2R)-2-Hydroxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate(4a)

To a solution of acetic acid(1R,2R)-benzyloxycyclohexyl-2,5-dioxo-pyrrolidin-3-(R)-yl ester (3a (1.1g, 3.18 mmol) in MeOH was added 10% Pd—C (110 mg), and the reactionvessel was flushed twice with H₂. The reaction mixture was agitated atambient temperature under H₂ (charged balloon). After 4 hours, thereaction mixture was filtered through a pad of Celite. The filtrate wasconcentrated in vacuo to give acetic acid1R,2R-hydroxycyclohexyl-2,5-dioxopyrrolidin-3-(R)-yl ester (4a) as awhite hygroscopic foam (0.82 g, 99% yield); MS (ES+) 256.1 [M+H]⁺, 278.0[M+Na]⁺, 533.1 [2M+Na]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 1.11-1.34 (m, 3H),1.64-1.75 (m, 3H), 2.02-2.09 (m, 2H), 2.12 (s, 3H, CH₃), 2.22 (br s,1H), 2.63 (dd, 1H, J=18.0 Hz, 4.8 Hz), 3.11 (dd, 1H, J=8.8 Hz, J=18 Hz),3.82 (ddd, 1H, J=4.16 Hz, J=10.6 Hz, J=12.8 Hz), 4.16 (ddd, 1H, J=4.4Hz, J=10.4 Hz, J=14.8 Hz), 5.34 (dd, 1H, J=8.8 Hz, J=4.8 Hz); ¹³C-NMR(100 MHz, CDCl₃) δ 20.52, 24.16, 24.98, 27.77, 35.03, 35.40, 58.44,67.43, 68.40, 170.11, 173.89, 174.08.

Preparation 4 3,4-(Dimethoxyphenethoxy)trichloracetimidate (5a)

To a reaction flask was charged 3,4-dimethoxyphenethyl alcohol (50 mL),and the resultant mixture was adjusted to 12° C. (9-15° C.). Solidpotassium hydroxide (5.0 g, 1.62 equiv), and methyltributylammoniumchloride (75 wt % solution in water; 0.4 g, 0.02 equiv) were charged tothe reaction flask. Under maximum agitation, trichloroacetonitrile (10.0g, 1.26 equiv) was charged slowly to the reaction flask via an additionfunnel, while the pot temperature was maintained <15° C. The reactionmixture was agitated at 12° C. (9-15° C.) for 1-4 hours. The reactionmixture was diluted with methyl tert-butyl ether (MTBE) (20 mL), thencooled to 3° C. (0-6° C.). Next, the MTBE layer was washed with water(3×20 mL) at 3° C. (0-6° C.). The MTBE solution was concentrated underreduced pressure to dryness at a maximum bath temperature of 40° C., andethanol (55 mL) was added to the remaining residue and the mixture wasagitated at 25° C. (22-28° C.) until a clear solution was achieved. Theethanolic solution was cooled to 0° C. (−3 to 3° C.) to allow productcrystallization. The slurry was diluted with water (77 mL) and themixture was agitated at 0° C. (−3 to 3° C.) for ˜1 h. The slurry wasfiltered and rinsed with cold (0-6° C.) water (36 mL). The wet cake wasdried under vacuum at ambient temperature (15-25° C.) until the moisturecontent (KF) was lower than 0.05% to give3,4-(dimethoxyphenethoxy)trichloracetimidate (5a), as an off-whitecrystalline solid (90-95% yield); ¹H-NMR (300 MHz, CDCl₃) δ 2.97 (t, 2H,J=7 Hz, CH₂), 3.81 & 3.79 (2 s, 6H, 2×OCH₃), 4.42 (t, 2H, J=7 Hz, CH₂O),6.77-6.75 (m, 3H, Ar), 8.22 (br s, 1H, NH).

PREPARATION 5 Acetic acid1R,2R-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5-dioxo-pyrrolidin-3R-ylester (6a)

A solution of acetic acid1R,2R-hydroxycyclohexyl-2,5-dioxopyrrolidin-3-(R)-yl ester (4a) (0.75 g,3.08 mmol) in toluene (8 mL) was cooled to 0° C. Tetrafluoroboric aciddiethyl ether complex (0.2 equiv, 87 μL) was charged to the flask andthe mixture was agitated at ambient temperature for ˜30 min. A solutionof 3,4-(dimethoxyphenethoxy)trichloracetimidate (5a) (1.05 g, 1.05equiv) in toluene (5 mL) was added via a syringe over 15-20 min. Thereaction mixture was agitated at ambient temperature until the reactionwas complete. On completion, the reaction mixture was cooled to −10° C.and the precipitated trichloroacetamide was filtered. The cake wasrinsed with cold toluene (10 mL), and the toluene filtrate was washedsuccessively with water (15 mL) and brine (15 mL). The organic layer wasdried (anhydrous MgSO₄), filtered, and concentrated under reducedpressure to give a light brown syrup. The crude product was purified byflash column chromatography (silica gel; EtOAc:hexane, 1:4 v/v) to giveacetic acid1R,2R-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5-dioxo-pyrrolidin-3R-ylester (6a) as a thick colorless syrup (0.92 g, 75% yield); MS (ES+)420.2 [M+H]⁺, 437.2 [M+H₂O]⁺, 442.2 [M+Na]⁺, ¹H-NMR (400 MHz, CDCl₃) δ1.10-1.33 (m, 3H), 1.61-1.75 (m, 3H), 1.91-2.02 (m, 1H), 2.07 (s, 3H),2.17-2.20 (m, 1H), 2.34 (dd, 1H, J=5.2 Hz, J=18 Hz), 2.59-2.76 (m, 3H),3.13 (ddd, 1H, J=5.6 Hz, J=8.8 Hz, J=14.4 Hz), 3.77-3.93 (m, 9H), 4.71(br s, 1H), 6.46-6.67 (m, 2H), 6.77-6.79 (m, 1H); ¹³C-NMR (100 MHz,CDCl₃) δ 20.35, 23.85, 24.87, 28.04, 30.88, 35.07, 35.84, 55.66, 55.70,55.72, 66.72, 68.81, 75.02, 110.95, 111.99, 112.52, 132.21, 147.09,148.29, 169.54, 173.16, 173.57.

PREPARATION 6 Preparation of Acetic acid1R,2R-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5-dioxo-pyrrolidin-3R-ylester (6a) via One-pot Process (Acylation, Etherification, andCyclization)

To a cold (0° C.) solution of 1R,2R-aminocyclohexanol (1a) (1.00 g, 8.68mmol) in dichloromethane (17.4 mL) under nitrogen was added2R-acetoxysuccinic anhydride (2a1) (1.44 g, 9.11 mmol). The reaction wasallowed to warm to ambient temperature and stirred for 1.5 h.3,4-(dimethoxyphenethoxy)trichloracetimidate (5a) (3.41 g, 10.4 mmol)was added in a single portion and the solution was subsequently cooledto 0° C. HBF₄ (359 μL, 54% in Et₂O, 2.60 mmol) was added and theresultant mixture was stirred for 2.5 h. Acetyl chloride (15 mL) wasadded via syringe, and the solution was raised to reflux for 1 h, andthen allowed to cool to ambient temperature prior to removal of solventin vacuo. The residue was taken up in ethyl acetate (25 mL) and water(25 mL), the organic layers were separated and the aqueous layerextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed successively with H₂O (25 mL) and brine (25 mL), dried with MgSO₄(anhydrous), filtered, and the solvent was removed in vacuo. Flashcolumn chromatography of the residue on silica gel (35% EtOAc/hexanes)yielded acetic acid1R,2R-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5-dioxo-pyrrolidin-3R-ylester (6a), as a viscous yellow oil (680 mg, 19% yield); MS (ES+) 420.1[M+H]⁺, 437.1 [M÷H₂O]⁺, 442.0 [M+Na]⁺.

Preparation 7 Preparation of(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Compound of formula (Ia))

To a solution of acetic acid1R,2R-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5-dioxo-pyrrolidin-3R-ylester (6a) (0.5 g, 1.19 mmol) in anhydrous THF (2 mL) was addedborane-THF complex solution (1 M, 8.0 mL) under N₂. The reaction mixturewas stirred at ambient temperature for 18 hours. The reaction mixturewas cooled to 0° C. and quenched slowly by addition of a solution ofMeOH (5.0 mL) saturated with HCl gas and concentrated under vacuum togive a pale yellow syrup. Trituration of the syrup in Et₂O (10 mL)afforded the monohydrochloride salt of(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ia) as an off-white solid (340 mg, 74% yield) with 79.5% HPLC purity;¹H NMR (400 MHz, D₂O): δ 7.05-7.02 (m, 2H), 6.94 (dd, 1H, J=2 Hz, 8 Hz),4.43-4.38 (m, 1H), 4.11-4.04 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.69(overlapping dt, 1H, J 6 Hz, 9 Hz), 3.50-3.40 (m, 1H), 3.31-3.01 (m,5H), 2.97-2.79 (m, 2H), 2.37-2.30 (m, 1H), 2.10-1.70 (m, 5H), 1.45-1.12(m, 4H).

Isomeric purity: 99.6% ee hydrochloride salt of(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ia) vs hydrochloride salt of(3R)-1-[(1S,2S)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ib)

Isomeric purity 4.02% of the hydrochloride salt of(3S)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ic) observed.

PREPARATION 8

In a similar manner as set forth above in Preparation 1-Preparation 7,the following compounds of formula (I) are prepared:

(3R)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol,(Compound of formula (Ib)), ¹H NMR (D₂O, 400 MHz) δ 7.06-7.01 (m, 2H),6.94 (dd, 1H, J=8, J=2), 4.43 (br s, 1H), 4.06 (overlapping dt, 1H, J=9,J=6), 3.87, 3.86 (two s, 2×3H), 3.75-3.67 (m, 1H), 3.52-2.80 (m, 8H),2.38-2.30 (m, 1H), 2.12-1.70 (m, 5H), 1.47-1.10 (m, 4H);

(3S)-1-[(1R,2R)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol,(Compound of formula (Ic)), ¹H NMR (D₂O, 400 MHz) δ 6.88-6.82 (m, 2H),6.78-6.73 (m, 1H), 4.29 (br s, 1H), 3.91-3.83 (m, 1H), 3.71, 3.69 (twos, 2×3H), 3.58-3.47 (m, 1H), 3.40-2.94 (m, 6H), 2.80-2.62 (m, 2H),2.22-2.10 (m, 1H), 2.03-1.55 (m, 5H), 1.32-0.95 (m, 4H); and

(3S)-1-[(1S,2S)-2-[2-(3,4-dimethoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol,(Compound of formula (Id)), ¹H NMR (D₂O, 400 MHz) δ 7.06-7.01 (m, 2H),6.95 (dd, 1H, J=8, J=2), 4.40 (br s, 1H), 4.12-4.03 (m, 1H), 3.88, 3.87(two s, 2×3H), 3.73-3.66 (m, 1H), 3.50-2.80 (m, 8H), 2.37-2.30 (m, 1H),2.10-1.73 (m, 5H), 1.45-1.10 (m, 4H).

Preparation 9(1R,2R)-1-{2-[2-(4-Benzyloxy-3-methoxy-phenyl)-ethoxy]-cyclohexyl}-(3R)-2,5-dioxo-pyrrolidin-3-yl acetate

A. To a solution of(3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (4a) (13.5 g, 53.1 mmol) in anhydrous toluene (80 mL) at 0° C.under a nitrogen atmosphere was added HBF₄.OEt₂ (3.40 g, 21.2 mmol, 2.90mL). The mixture was stirred for 15 minutes and a solution of2-(4-benzyloxy-3-methoxyphenyl)ethyl-2,2,2-trichloroacetimidate (23.5 g,58.4 mmol) in anhydrous toluene (100 mL) was added via an additionfunnel over a period of 30 minutes. The solution was allowed to warm toambient temperature and stirred for 3 hours. Water (100 mL) was thenadded and stirred for 15 minutes. 10% aqueous NaHCO₃ (10 mL) was alsoadded slowly and stirred until no more bubbling was observed. Themixture was then transferred to a separatory funnel and the layers wereseparated. The organic phase was washed successively with 10% aqueousNaHCO₃ (3×150 mL), water (150 mL), and brine (100 mL). The organic phasewas dried over Na₂SO₄, filtered, and concentrated. The residue wasdissolved in toluene (200 mL) and cooled to −20° C. for 18 h toprecipitate the trichloroacetamide by-product. The mixture was filteredand the filtrate was concentrated.

B. The above procedure was repeated with(3R)-1-(1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate(30.5 g, 0.120 mol). The crude product from the two reactions werecombined and purified by column chromatography (hexanes-EtOAc, 4:1,v/v). The product from the chromatography was dissolved in toluene (200mL) and cooled to −20° C. for 48 hours to precipitate out the remainingtrichloroacetamide by-product. The mixture was filtered and the filtratewas concentrated to afford(1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-2,5-dioxopyrrolidin-3-ylacetate (49.5 g, 58% combined yield) as a light yellow oil; MS (ESI):496.1 [M+H]⁺, 518.1 [M+Na]⁺.

Preparation 10(1R,2R)-1-{2-[2-(4-Benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-olhydrochloride

To a solution of(1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]-cyclohexyl}-(3R)-2,5-dioxopyrrolidin-3-ylacetate (49.0 g, 100 mmol) in anhydrous THF (100 mL) under nitrogen wasadded slowly BH₃.THF (1.0 M solution in THF, 400 mmol, 400 mL). Thesolution was heated to 80° C. and stirred for 3 hours. The solution wascooled to ambient temperature and methanol (100 mL) was added slowlyuntil no more bubbling was observed. The solution was concentrated andmethanolic HCl (1.25 M solution in CH₃OH, 500 mL) was added. Thesolution was heated to 80° C. and stirred for 1 hour. The cooledsolution was then concentrated to afford(1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-olhydrochloride (50.8 g, quantitative yield) as a yellow syrup. The crudeproduct was used in the next step without further purification; ¹H NMR(400 MHz, CDCl₃) δ 11.45 (br, s, 1H), 7.50-7.10 (m, 5H), 6.90-6.60 (m,3H), 4.22 (br, s, 1H), 4.00-3.85 (m, 5H), 3.75-3.55 (m, 2H), 3.35-2.50(m, 7H), 2.45-2.20 (m, 2H), 2.08 (br, s, 1H), 1.90-1.50 (m, 3H),1.35-1.05 (m, 6H); MS (ESI): 426.2 [M+H]⁺

Preparation 11(3R)-1-[(1R,2R)-2-[2-(4-Hydroxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Compound of formula (Ie))

A solution of compound(1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-ol(50.3 g, 100 mmol) in methanol (250 mL) was transferred to a Parr shakerbottle that has previously been charged with Pd/C (10% wt/wt, 4.0 g) asa slurry in water. The bottle was placed on a Parr hydrogenator andevacuated. Hydrogen pressure (60 psi) was then applied and the vesselwas shaken for 1 hour. The mixture was filtered through a pad of Celiteand the filtrate was concentrated. The residue was dissolved in water(250 mL) and washed successively with ethyl acetate (3×200 mL) andchloroform (10×150 mL). The aqueous solution was saturated with NaCl andwashed with dichloromethane (4×200 mL). The combined organic extract wasconcentrated and 5% aqueous NaHCO₃ (200 mL) was added to the residue.The suspension was stirred for 30 minutes and then extracted with ethylacetate (8×250 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated to afford a yellowishpowder. The powder was then triturated with ethyl acetate (3×50 mL) andsubjected to high vacuum (oil pump) to afford(3R)-1-[(1R,2R)-2-[2-(4-hydroxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(15.6 g, 43% yield) as a white powder; ¹H NMR (400 MHz, CDCl₃) δ 6.82(d, 1H, J=8.0), 6.75 (br s, 1H), 6.70 (d, 1H, J=8.0), 4.30-4.20 (m, 1H),3.87 (s, 3H), 3.78-3.70 (m, 1H), 3.56 (q, 1H), 3.33 (td, 1H, J=7.6,J=3.6), 2.97-2.89 (m, 1H), 2.84-2.75 (m, 3H), 2.65 (dd, 1H, J=10,J=5.2), 2.55-2.38 (m, 2H), 2.09-1.95 (m, 2H), 1.91-1.82 (m, 1H),1.73-1.58 (m, 3H), 1.41-1.15 (m, 4H); ¹³C-NMR (100 MHz, CDCl₃) δ 23.25,23.68, 27.59, 29.21, 34.42, 36.70, 48.84, 56.06, 59.93, 63.68, 69.83,71.29, 79.59, 111.98, 114.60, 121.65, 131.35, 144.23, 146.67; IR: 3436(O—H stretch), 1591, 1515, 1272, 1098, 1030, 851 cm⁻¹; MS (ESI) 336.2(M+1)⁺.

Preparation 12(1R,2R)-1-{2-[2-(3-Benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxo-pyrrolidin-3-(R)-ylacetate

To a chilled (0° C.) solution of(3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (15.0 g, 58.7 mmol) in anhydrous dichloromethane (100 mL) wasadded tetrafluoroboric acid diethyl ether complex (3.2 mL). Theresultant reaction mixture was stirred at 0° C. for 20 minutes beforeadding a solution of2-(3-benzyloxy-4-methoxy-phenyl)-ethyl-2,2,2-trichloroacetimidate (24.8g, 61.6 mmol, 1.05 equiv.) in dichloromethane (100 mL) via an additionfunnel over 30 minutes. The reaction mixture was stirred at 0° C. untilthe reaction was judged complete by HPLC analysis. The reaction mixturewas quenched with water (250 mL). The organic layer was separated fromthe aqueous layer and subsequently washed with dilute NaHCO₃ (5% wtsolution, 2×100 mL), and water (5×100 mL). The organic layer was dried(anhydrous MgSO₄), filtered, and concentrated under reduced pressure to˜100 mL solution. The solution was cooled at −20° C. for 24 hours andthe precipitate (trichloroacetamide) was removed by filtration. Thefiltrate was further concentrated to a volume of ˜40 mL. This processwas repeated three times until the bulk of the by-product(trichloroacetamide) was removed. After the third filtration, thefiltrate was concentrated in vacuo to give(1R,2R)-1-{2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-ylacetate as a pale yellow syrup (25 g, 86% yield).

Preparation 13(3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinolhydrochloride

To a solution of(1R,2R)-1-{2-[2-(3-Benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-ylacetate (42.0 g, 84.8 mmol) in anhydrous THF (300 mL) at 0° C. was addedborane-THF complex solution (1.0 M, 297 mL, 3.5 mol equivalents) underN₂ via an addition funnel over a period of 60 minutes. The reactionmixture was heated to reflux for 60 minutes. The reaction mixture wascooled to 0° C. and quenched slowly by addition of methanol (˜15 mL).The reaction mixture was concentrated under reduced pressure to removethe THF and to the residue was added methanolic-HCl solution (˜1.25 M inmethanol, 297 mL, 3.5 equivalents). The solution was then heated at70-80° C. for 2 hours. The reaction mixture was cooled to ambienttemperature and concentrated under reduced pressure to give(3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinolhydrochloride as a colorless syrup (35.0 g, 89% yield). The sample wasused directly without further purification in the next step.

Preparation 14(3R)-1-[(1R,2R)-2-[2-(3-Hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Compound of formula (If))

To compound(3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(35.0 g, 75.8 mmol) was added methanol (150 mL). This solution wastransferred to a Parr bottle and Pd/C (10% wt/wt on activated carbon)was added portion-wise while maintaining a N₂ atmosphere through thereaction mixture. Hydrogen pressure (60 psi) was then applied and thevessel shaken for 3 hours, after which HPLC showed complete consumptionof the starting material. The reaction mixture was filtered through apad of Celite and the filtrate was concentrated to give(3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinolas a colorless syrup. The crude product was dissolved in 1 M aqueous HClsolution (450 mL) and washed with chloroform (8×250 mL). The aqueouslayer was then saturated with solid NaCl (100 g) and the solution wasextracted with dichloromethane (8×200 mL). The combined dichloromethaneextracts were dried (anhydrous MgSO₄), filtered, and concentrated underreduced pressure to give3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinolas a colorless syrup; ¹H NMR (400 MHz, D₂O) δ 7.01 (d, H, J=8.0),6.86-6.83 (m, 2H), 4.42-4.36 (m, 1H), 4.02 (overlapping dt, 1H, J=5.2,J=10.1), 3.85 (s, 3H), 3.67-3.55 (m, 1H), 3.46-2.81 (m, 7H), 2.77-2.70(m, 1H), 2.34-2.27 (m, 1H), 2.11-1.74 (m, 5H), 1.41-1.10 (m, 4H); IR:3439 (O—H stretch), 1592, 1510, 1098, 1022 cm⁻¹; MS (ESI) 336.1 (M+1)⁺.

PREPARATION 15

In a similar manner as set forth above in Preparation 9-Preparation 14,but using the appropriately substituted starting materials, thefollowing compounds of formula (1) were prepared:

-   (3R)-1-[(1R,2R)-2-[2-(4-ethoxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol,    (Compound of formula (Ig)); and-   (3R)-1-[(1R,2R)-2-[2-(3-ethoxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol    (Compound of formula (Ih)).

Preparation 16(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Preparation of Compound of Formula (Ia) without Solvent Exchange)

A. To a stirred solution of (1R,2R)-2-benzyloxycyclohexylamine (1) (125g, 0.609 mol) in toluene (1620 g) was added 2R-acetoxysuccinic anhydride(2a1) (129 g, 0.816 mol, 1.34 equiv.) in small portions as a solid. Thereaction mixture was stirred at 65° C. under inert atmosphere. After 4hours stirring, no starting material was observed by HPLC. The reactionmixture was cooled to 48-50° C. and acetyl chloride (107 g, 1.37 mol,2.24 equiv.) was added. The mixture was heated to 60° C. giving a clearsolution and was stirred at the latter temperature for further 3 hours.The reaction mixture was cooled to ambient temperature. After allowingto stand at ambient temperature for 16 hours, the excess of acetylchloride was distilled off at ambient pressure. The distillation wasstopped until the boiling point reached a temperature of ca. 105° C.From the reaction mixture was distilled 172 g (acetyl chloride andtoluene) off to receive 1714 g of(3R)-1-((1R,2R)-2-benzyloxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (3a) in toluene.

B. To a solution of(3R)-1-((1R,2R)-2-benzyloxycyclohex-1-yl)-2,5-dioxopyrrolidin-3-ylacetate (3a) in toluene (446 g, 0.151 mol) was added 10% Pd/C (6.3 g, 50wt-% water wet), and the reaction vessel was flushed twice with H₂. Thereaction mixture was agitated at 18° C. under H₂ (5 bar) for 8 hours andat 45° C. under H₂ (5 bar) for 15.5 hours. The progress of the reactionwas monitored by HPLC. The reaction mixture was filtered, the filtratewas washed with toluene and the filtrate was concentrated in vacuo togive 3-(R)-1-[(1R,2R)-2-hydroxycyclohexyl]-2,5-dioxopyrrolidin-3-ylacetate (4a) as a white hygroscopic foam (46.0 g).

C. To a cooled (0° C.) solution of3-(R)-1-[(1R,2R)-2-hydroxycyclohexyl]-2,5-dioxopyrrolidin-3-yl acetate(4a) (120.6 g) in 800 g toluene was added 12.5 g tetrafluoroboric aciddiethyl ether. After addition the solution was allowed to warm up to 20°C. Then 171 g of 3,4-(dimethoxyphenethoxy)trichloracetimidate (5a) (0.54mol) in toluene (600 g) was added over a period of 1 hour. The reactionmixture was allowed to stir for further 30 min until the reaction wasjudged to be complete by HPLC. On completion, the reaction mixture wascooled to −15° C. and the precipitated trichloroacetamide was filtered.The filtrate was washed with water (5×100 g). From the organic layer apart of the solvent was distilled off to receive a dry organic productsolution of3-(R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}-2,5-dioxo-pyrrolidin-3-ylacetate (6a). To the solution was added 10 g toluene to receive 471.5 gsolution, which contains 29.9% of3-(R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}-2,5-dioxo-pyrrolidin-3-ylacetate (6a) (141 g).

D. To the cooled (0° C.) solution of3-(R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl}-2,5-dioxo-pyrrolidin-3-ylacetate (6a) (29.9% in toluene) was slowly added a solution ofborane-THF complex (1 M, 3.5 mol eq., 1016 g) under N₂ over a period of3.5 hours. The reaction mixture was heated at reflux for 1 h. Thereaction mixture was cooled to 0° C. and slowly quenched by the additionof a methanolic-HCl solution (˜2.5 M in methanol, 373 g). The solutionwas then heated at reflux for 2 hours (62-66° C.) and the hydrolysis ofthe borane complex was monitored by HPLC. The reaction mixture wascooled to ambient temperature and concentrated under reduced pressure toobtain(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ia) as a pale yellow syrup. The crude product was dissolved in water(1192 g) and the organic layer was washed with a mixture of methylenechloride/chlorobenzene (1:1; v/v) 4 times. The aqueous layer was thensaturated with solid NaCl (316 g) and the solution was extracted withdichloromethane (2×930 g). The combined organic layers were dried(anhydrous MgSO₄, 223 g, 8 h), filtered, and concentrated under reducedpressure to give(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ia) as an off-white syrup, which solidified to a white foam upon dryingunder vacuum. The product was dissolved in isopropyl alcohol (279 g) atreflux, and then a part was distilled off (184.5 g) to receive 170.5 gproduct solution. To ⅔ of this solution (=114 g) isopropyl acetate (250g) was added, then the solution was allowed to cool to 5° C. for 4 hoursto form a crystalline solid which was filtered and dried under vacuum atambient temperature for 48 hours to obtain 6.5 g of(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol(Ia).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptatios, changes, modifications,substitutions, deletions or additions of procedures and protocols may bemade without departing from the spirit and scope of the invention. It isintended, therefore, that the invention be defined by the scope of theclaims which follow and that such claims be interpreted as broadly as isreasonable to one skilled in the art.

1. A method of making a compound of formula (I):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, stereoisomer, metabolite or prodrugthereof; as a single stereoisomer or as a mixture thereof; wherein: R³,R⁴ and R⁵ are independently bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano,sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃, C₂-C₇alkanoyloxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,C₁-C₆thioalkyl, aryl or —N(R₆)R₇; and R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from hydrogen, acetyl, methanesulfonyl orC₁-C₆alkyl; which method comprises the following: a) reacting a compoundof formula (1a):

with a compound of formula (2a):

under suitable condensation conditions to form a product; b) reactingthe product of a) with a compound of formula (5):

wherein Q is a leaving group and R³, R⁴ and R⁵ are as defined above,under suitable ether coupling conditions to form a product; c) reactingthe product of b) under suitable cyclization conditions to form acompound of formula (6):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R is H,C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ and R⁵ are as definedabove; and d) reducing the compound of formula (6) under suitableconditions to form a compound of formula (I), as set forth above.
 2. Themethod of claim 1 wherein the product of a) comprises a compound offormula (9), a compound of formula (10) or a mixture of a compound offormula (9) and a compound of formula (10):

where each R^(2a) is O or H₂ and R is H, C₂-C₅acyl or anoxygen-protecting group.
 3. The method of claim 1 or claim 2 wherein theproduct of b) comprises a compound of formula (11), a compound offormula (12) or a mixture of a compound of formula (11) and a compoundof formula (12):

where each R^(2a) is O or H₂, R is H, C₂-C₅acyl or an oxygen-protectinggroup and R³, R⁴ and R⁵ are as defined above.
 4. The method of claim 1further comprising the formation of an acid addition salt of thecompound of formula (I).
 5. The method of claim 1 wherein the compoundof formula (I) is a compound of formula (I) where R³, R⁴ and R⁵ areindependently hydrogen, hydroxy or C₁-C₆alkoxy; with the proviso thatR³, R⁴ and R⁵ cannot all be hydrogen at the same time.
 6. The method ofclaim 5 wherein the compound of formula (I) is a compound of formula(Ia):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof.
 7. Themethod of claim 5 wherein the compound of formula (1) is selected fromthe group consisting of:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof.
 8. A method of making a compound of formula (I):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, stereoisomer, metabolite or prodrugthereof, as a single stereoisomer or as a mixture thereof; wherein: R³,R⁴ and R⁵ are independently bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano,sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃, C₂-C₇alkanoyloxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,C₁-C₆thioalkyl, aryl or —N(R₆)R₇; and R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from hydrogen, acetyl, methanesulfonyl orC₁-C₆alkyl; which method comprises: a) reacting a compound of formula(17):

wherein R³, R⁴ and R⁵ are as defined above, with a compound of formula(2a2):

wherein R is H, C₂-C₅acyl or an oxygen-protecting group, under suitablecondensation conditions to form a compound of formula (6b):

wherein R is H, C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ andR⁵ are as defined above; and b) reducing the compound of formula (6b)under suitable conditions to form a compound of formula (I), as setforth above.
 9. The method of claim 8 further comprising a nucleophilicdisplacement step to form the compound of formula (17), wherein thenucleophilic displacement step comprises treating a compound of formula(16):

wherein —OR′ is an activated leaving group and R³, R⁴ and R⁵ are asdefined above, with an azide under suitable nucleophilic displacementand subsequent reduction conditions to form a compound of formula (17)as set forth above.
 10. The method of claim 9 further comprising apreparation step to form the compound of formula (16), wherein thepreparation step comprises reacting a compound of formula (15):

wherein R³, R⁴ and R⁵ are as described above, with an activating agentunder suitable conditions to form the compound of formula (16) as setforth above.
 11. The method of claim 10 wherein the activating agent isan optionally substituted alkylsulfonyl halide or an optionallysubstituted arylsulfonyl halide.
 12. The method of claim 10 furthercomprising an asymmetric reduction step to form a compound (15), whereinthe asymmetric reduction step comprises treating a compound of formula(14):

wherein R³, R⁴ and R⁵ are as defined above, under asymmetricreduction/hydrogenation conditions to form the compound of formula (15)as set forth above.
 13. The method of claim 12 further comprising anetherification step to form a compound of formula (14), wherein theetherification step comprises treating a compound of formula (13):

with a compound of formula (5b):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (14), as set forth above.
 14. The method ofclaim 8 further comprising the formation of an acid addition salt of thecompound of formula (I).
 15. The method of claim 8 wherein the compoundof formula (I) is a compound of formula (I) where R³, R⁴ and R⁵ areindependently hydrogen, hydroxy or C₁-C₆alkoxy; with the proviso thatR³, R⁴ and R⁵ cannot all be hydrogen at the same time.
 16. The method ofclaim 15 wherein the compound of formula (I) is a compound of formula(Ia):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof.
 17. Themethod of claim 15 wherein the compound of formula (I) is selected fromthe group consisting of:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof.
 18. A method of making a compound of formula (II):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, stereoisomer, metabolite or prodrugthereof; as a single stereoisomer or as a mixture thereof; wherein: R³,R⁴ and R⁵ are independently bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano,sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃, C₂-C₇alkanoyloxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,C₁-C₆thioalkyl, aryl or —N(R₆)R₇; and R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from hydrogen, acetyl, methanesulfonyl orC₁-C₆alkyl; which method comprises: a) reacting a compound of formula(20):

wherein each R^(2a) is O or H₂ where at least one R^(2a) in the compoundof formula (20) is O, and R is H, C₂-C₅acyl or an oxygen-protectinggroup, with a compound of formula (5):

wherein R³, R⁴ and R⁵ are as defined above and Q is a leaving group, toform a compound of formula (21):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R is H,C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ and R⁵ are as definedabove, under suitable conditions such that upon reaction of the compoundof formula (20) with the compound of formula (5), the cis relativeconfiguration of the hydroxyl group on the carbon at the 1-position ofthe compound of formula (20) is retained in the carbon at the 1-positionof the compound of formula (21); b) reducing the compound of formula(21) under suitable conditions to form a compound of formula (II). 19.The method of claim 18 further comprising a deprotection step prior tothe reaction of a compound of formula (20) with a compound of formula(5), wherein the deprotection step comprises treating a compound offormula (19):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R¹ is anoxygen-protecting group and R is H, C₂-C₅acyl or an oxygen-protectinggroup, to suitable deprotecting conditions to form a compound of formula(20) as set forth above.
 20. The method of claim 19 wherein R¹ is anoptionally substituted benzyl group and R is C₂-C₅acyl.
 21. The methodof claim 19 further comprising a cyclization step to form a compound offormula (19), wherein the cyclization step comprises reacting a compoundof formula (23) or a compound of formula (24) or a mixture of a compoundof formula (23) and a compound of formula (24):

wherein each R¹ is independently an oxygen-protecting group, each R^(2a)is O or H₂, and R is H, C₂-C₅acyl or an oxygen-protecting group, undersuitable conditions to form a compound of formula (19) as set forthabove.
 22. The method of claim 21 wherein R¹ is an optionallysubstituted benzyl group and R is C₂-C₅acyl.
 23. The method of claim 21further comprising a condensation step to form a compound of formula(23) or a compound of formula (24) or a mixture of a compound of formula(23) and a compound of formula (24), wherein the condensation stepcomprises reacting a compound of formula (18):

where R¹ is an oxygen-protecting group, with a compound of formula (2a):

wherein each R^(2a) is O or H₂ where at least one R^(2a) is O, R is H,C₂-C₅acyl or an oxygen-protecting group, under suitable conditions toform the compound of formula (23) or the compound of formula (24) or themixture of a compound of formula (23) and a compound of formula (24) asset forth above.
 24. The method of claim 23 wherein R¹ is an optionallysubstituted benzyl group and R is C₂-C₅acyl.
 25. The method of claim 18further comprising the formation of an acid addition salt of thecompound of formula (II).
 26. The method of claim 18 wherein thecompound of formula (II) is a compound of formula (II) where R³, R⁴ andR⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy; with the provisothat R³, R⁴ and R⁵ cannot all be hydrogen at the same time.
 27. Themethod of claim 26 wherein the compound of formula (I) is a compound offormula (IIa):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof.
 28. Themethod of claim 26 wherein the compound of formula (II) is selected fromthe group consisting of:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof.
 29. A method of making a compound of formula (II):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, stereoisomer, metabolite or prodrugthereof; as a single stereoisomer or as a mixture thereof; wherein: R³,R⁴ and R⁵ are independently bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano,sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃, C₂-C₇alkanoyloxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,C₁-C₆thioalkyl, aryl or —N(R₆)R₇; and R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from hydrogen, acetyl, methanesulfonyl orC₁-C₆alkyl; which method comprises the following: a) reacting a compoundof formula (22):

with a compound of formula (2a):

under suitable condensation conditions to form a product; b) reactingthe product of a) with a compound of formula (5):

wherein Q is a leaving group and R³, R⁴ and R⁵ are as defined above,under suitable ether coupling conditions to form a product; c) reactingthe product of b) under suitable cyclization conditions to form acompound of formula (21):

wherein each R^(2a) is O or H₂, R is H, C₂-C₅acyl or anoxygen-protecting group and R³, R⁴ and R⁵ are as defined above; andreducing the compound of formula (21) under suitable conditions to forma compound of formula (II), as set forth above.
 30. The method of claim29 wherein the product of a) comprises a compound of formula (25), acompound of formula (26) or a mixture of a compound of formula (25) anda compound of formula (26):

where each R^(2a) is O or H₂ and R is H, C₂-C₅acyl or anoxygen-protecting group.
 31. The method of claim 29 or claim 30 whereinthe product of b) comprises a compound of formula (27), a compound offormula (28) or a mixture of a compound of formula (27) and a compoundof formula (28):

where each R^(2a) is O or H₂, R is H, C₂-C₅acyl or an oxygen-protectinggroup and R³, R⁴ and R⁵ are as defined above.
 32. The method of claim 29further comprising the formation of an acid addition salt of thecompound of formula (II).
 33. The method of claim 29 wherein thecompound of formula (II) is a compound of formula (II) where R³, R⁴ andR⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy; with the provisothat R³, R⁴ and R⁵ cannot all be hydrogen at the same time.
 34. Themethod of claim 33 wherein the compound of formula (II) is a compound offormula (IIa):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof.
 35. Themethod of claim 33 wherein the compound of formula (II) is selected fromthe group consisting of:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof.
 36. A method of making a compound of formula (II):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, stereoisomer, metabolite or prodrugthereof, as a single stereoisomer or as a mixture thereof; wherein: R³,R⁴ and R⁵ are independently bromine, chlorine, fluorine, carboxy,hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano,sulfamyl, trifluoromethyl, —CHF₂, —SO₂N(R₈)R₉, —OCF₃, C₂-C₇alkanoyloxy,C₁-C₆alkyl, C₁-C₆alkoxy, C₇-C₁₂aralkoxy, C₂-C₇alkoxycarbonyl,C₁-C₆thioalkyl, aryl or —N(R₆)R₇; and R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from hydrogen, acetyl, methanesulfonyl orC₁-C₆alkyl; which method comprises: a) reacting a compound of formula(33):

wherein R³, R⁴ and R⁵ are as defined above, with a compound of formula(2a2):

wherein R is H, C₂-C₅acyl or an oxygen-protecting group, under suitablecondensation conditions to form a compound of formula (21b):

wherein R is H, C₂-C₅acyl or an oxygen-protecting group and R³, R⁴ andR⁵ are as defined above; and b) reducing the compound of formula (6b)under suitable conditions to form a compound of formula (II), as setforth above.
 37. The method of claim 36 further comprising anucleophilic displacement step to form the compound of formula (33),wherein the nucleophilic displacement step comprises treating a compoundof formula (32):

wherein —OR′ is an activated leaving group and R³, R⁴ and R⁵ are asdefined above, with an azide under suitable nucleophilic displacementand subsequent reduction conditions to form a compound of formula (33)as set forth above.
 38. The method of claim 37 further comprising apreparation step to form the compound of formula (32), wherein thepreparation step comprises reacting a compound of formula (31):

wherein R³, R⁴ and R⁵ are as described above, with an activating agentunder suitable conditions to form the compound of formula (32) as setforth above.
 39. The method of claim 38 wherein the activating agent isan optionally substituted alkylsulfonyl halide or an optionallysubstituted arylsulfonyl halide.
 40. The method of claim 38 furthercomprising a reduction step to form a compound (31), wherein thereduction step comprises treating a compound of formula (14):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (31) as set forth above.
 41. The method ofclaim 40 further comprising an etherification step to form a compound offormula (14), wherein the etherification step comprises treating acompound of formula (13):

with a compound of formula (5b):

wherein R³, R⁴ and R⁵ are as defined above, under suitable conditions toform the compound of formula (14), as set forth above.
 42. The method ofclaim 36 further comprising the formation of an acid addition salt ofthe compound of formula (II).
 43. The method of claim 36 wherein thecompound of formula (II) is a compound of formula (II) where R³, R⁴ andR⁵ are independently hydrogen, hydroxy or C₁-C₆alkoxy; with the provisothat R³, R⁴ and R⁵ cannot all be hydrogen at the same time.
 44. Themethod of claim 43 wherein the compound of formula (II) is a compound offormula (IIa):

or a pharmaceutically acceptable salt, ester, amide, complex, chelate,clathrate, solvate, polymorph, metabolite or prodrug thereof.
 45. Themethod of claim 44 wherein the compound of formula (I) is selected fromthe group consisting of:

or pharmaceutically acceptable salts, esters, amides, complexes,chelates, clathrates, solvates, polymorphs, metabolites or prodrugsthereof.